Potential Mechanism of Action of Intra-articular Hyaluronan Therapy in Osteoarthritis: Are the Effects Molecular Weight Dependent? P e t e rG h o s h a n d D i e g o G u i d o l i n Background:Hyaluronan,or hyaluronicacid (HA),is the maior hydrodynamic nonprotein component of joint synovial fluid (SF). lts unique viscoelastic propertiesconfer remarkableshock absorbingand lubricatingabilitiesto SF, sizeand hydrophilicityserveto retainfluid while its enormousmacromolecular in the joint cavity during articulation.HA restrictsthe entry of large plasma proteinsand cellsinto SF but facilitatessolute exchangebetweenthe synovial capillariesand cartilageand other joint tissues. In addition, HA can form a pericellularcoat around cells,interact with proinflammatorymediators,and bind to cell receptors,such as cluster determinant (CD)44and receptor for hyaluronate-mediated motility (RHAMM),where it modulates cell proliferation, migration,and gene expression.All these physicochemicaland biologic propertiesof HA have been shown to be molecularweight (MW) dependent. Objective:Intra-articular(lA) HA therapy has been used for the treatment of knee osteoarthritis(OA) for more than 30 years. However,the mechanisms responsiblefor the reported beneficialclinical effects of this form of treatment remain contentious. Furthermore,there are a variety of pharmaceuticHA preparationsof different MW available for the treatment of OA, but the significanceof their MWs with respectto their pharmacologicactivitieshave not been reviewed previously.The objective of the present review is to redress this deficiency. Methods: We reviewed in vitro and in vivo reports to identify those pharmacologicactivitiesof HA that were consideredrelevantto the ability of this agent to relievesymptoms and protect joint tissues in OA. Where possible, reports were selectedfor inclusionwhen the pharmacologiceffects of HA had been studied in relationto its MW. In many studies,only a single HA preparation had been investigated.In these instances,the experimentaloutcomes reportedwere comparedwith similarstudiesundertakenwith HAs of different MWs. Results:Although in vitro studieshave generallyindicatedthat high MW-HA preparationswere more biologicallyactivethan HAs of lower MW, this finding was not confirmedusing animal models of OA. The discrepancymay be partly explained by the enhanced penetration of the lower MW HA preparation through the extracellularmatrix of the synovium, thereby maximizing its concentrationand facilitatingits interactionwith target synovial cells. However,there is accumulatingexperimentalevidenceto show that the binding of HAs to their cellularreceptorsis dependenton their molecularsize;the smaller F rortt Iltt' Irt.stiîureol []tne ulkl Joirû Rt'.tcttrtlt. I)epurtntettl Rotul Nortlt Shore Httspitnl, Ncrr' .lorrllr \\'ule.s. Aust ntl itt: tunl O.stt'o-Att it ukLr D i y i.stot t, of'.Surgtrr. [,IrrÀz,rsln o/ Srûicr'. Fitliu S.p.A. Abtuu Petel Ghosh. I)Sc. PhD. FRACI. FRSC: A:sot'iutt, Proles:or. {,rrlit,rsitl Reseuxlt, Dtpurtntettt of Sll.qen. o/ Srr/nar', Ro.tul Nortlt Slnrt' Hospitul. St. Lco- r r r u z 1 . rN , c r r S o u t l t l V u l e . s ., 1 u . \ t r u l i u : D i c g o G u i d o l i n . P h l ) : O.stett-Artitrtiur Diri:irttt. Fidia S.p.A. ,\butut Tennt, Itul.t. 10 tttt.s ptLrtiulh liuiletl ,lrhlress n'l)rint r?qu(tt.\ to A.\so(iutt Proltssrtr Pcrtr Glut.sh. Irt.;riure ol Botrc tuil .loirtt Reseurtlt Level 5, Univer;itv Clittit, Terntt'. Itulv. lttstitute ol Rotte uil.loirtr Rt'.st'urtlt lor ltrt'lttrrtLriott tl tltis rtritt S.p.A. Alttno lertne, ltult. bv Filiu Blotk 825-Fitul North Slnre Ho.sltitul, St. Letnrunls. À'r'rl Soiait ll'ttle.s. 2065. Austruliu. E-rtruil: ltghorh(4:nnil.u.st tl.edu.urr ('optri,ght )002, Elstvier Scit'ttt't'(LISA). ;\ll i,qlts rc.senvtl. u )19-()I 72/02/-1 201-()0()-r.$5.()(y0 -t/surh.2U)2.-12519 ù i: 10.105 Seminars in Arthritis and Rheumatism,Yol 32, No 1 iAugust), 2002: pp 10-37 INTRA-ARTICULA HR YALURONAN T H E R A P YI N O S T E O A R T H R I T I S HA molecularspeciesoften elicits an opposite cellularresponseto that produced by the higher MW preparations.Studies using large animal models of OA have shown that HAs with MWs within the range of 0.5 x 106-1.0x 106Da were generallymore effectivein reducingindicesof synovialinflammationand restoring the rheologicalproperties of SF (visco-induction)than HAs with MW > 2.3 x 106Da. Theseexperimentalfindings were consistentwith light and electron microscopicstudies of synovial membrane and cartilagebiopsy specimensobtainedfrom OA patientsadministered5 weekly lA injectionsof HA of MW = 0.5 x 106-0.73 x 106Da in which evidenceof partialrestorationof normal joint tissue metabolismwas obtained. Conclusions;By mitigating the activities of proinflammatory mediators and pain producing neuropeptidesreleasedby activated synovial cells, HA may improve the symptoms of OA. In addition,HAs within the MW range of 0.5 x 106-1.0x 106 Da partially restore SF rheological properties and synovial fibroblastmetabolismin animal models.Thesepharmacologicactivitiesof HA could accountfor the reportedlong-termclinicalbenefitsof this OA therapy. However, clinical evidence has yet to be describedto support the animal studiesthat indicatedthat HAs with MW > 2.3 x 106Da may be lesseffective in restoringSF rheologythan HAs of half this size. Semin Arthritis Rheum 32:10-37.Copyright 2002, Elsevier Science (USA). All rights reserved. INDEXWORDS:Hyaluronan;molecularweight; osteoarthritis;pharmacology. o l h v a l u r o n i ca c i c l ( H A ) . fI-YALURONAN. lI is the rnost abundant-ulycosantinoglycan ( G A G ) i n m a m m a l i a nt i s s L r eI t. i s p r e s e nitn h i g h c o n c e n t r a t i o ni ns c o n n e c t i v e t i s s u e .s u c ha s s k i n . vitreoushumor. cartilage.and umbilicalcord. but the largest single reservoiris the synovial lluid (SF) of tl.recliarthrodialjoints. where concentra( 1.2t.The high tions of 0.5-,1rng/ntl-nre achievecl concentration of HA in SF is essentialfirl normal joint function. becauscHA conlèr'serceptional visco-elasticityand lubricatingpropcrtiesto SF. particularll,during hi.ehshearcgncliti6ns.Uncler dynarnicloadingof diarthrodialjoints. shearthinning and a reductionin r,iscosityoccurbecauseof decreasep d h y s i c a le n t a n s l e m e n tosf H A n t o l e cules ancl their realignlltentto clirectionsntole parallelwith the axis of articulation.TheseLrniclue non-Newtonianrheologicalproperticsof HA not only reducewear anciattritionof articularcaltilage r tl s os t a b i l i z ej o i n t sa t d u r i n gj o i n t m o t i o n( 3 - 5 1 b L a low shearlates (6). In addition.the high exclusionproperries of HA moleculesrestrictthe entry of plasrnaproteinsintct the aqueousphaseof SF. This excltLsion eftèct is dependenton the molecularwei-eht(MW) rlf the ploteins;ie. lar-lemolecules(suchasplasrnaalpha- 2-macroglobuIin) essentially ale exclnclecl thtrr the S F w a t e r s p a c e( 7 . 8 ) .B y c o n t r a s tH . A facilitates the transportof u'ilterand small solutesthroughSF to articLrlar cartila-ce fiom capillariesin the syno(lA) viunr and reclucesfluiclloss as intra-articr-rlar' pressureis raisec'l during.jointflcxion (8- | 0). Thcse propertiesof HA are importantfbr the nLrtlitionof iu'ticularcartila-ce as well as tbr the climinationof metabolitesanclnoxioussubstances from the .jornt cavity. HA MOLECULAR STRUCTURE T h e d i r c r s c p h v s i c o c h c r n i cparl o p e r t i e o sf HA alise flont its unicluernercromolecular strLlcture. Thc HA is an cxceptionallylon-u(3-30 g.nt) and unbranchecl nonsulfitted GAC conrposecl of' repeating disaccharicle r-rnits N-acetyl-elucosarnine. of and - u l u c u l o n iacc i dg l y c o s i d i c a l llyi n k e ctlh r o u g ht h e r r r c s p e c t i v el - . 1r i n - gp o s i t i o n s( F i - gI ) . groupoxygensat the -ulucuronvlHy'clroxyl l ancl slucosamine3-positiilnsare usedfbr furtherpol1,merizationof the HA disaccharideunits to tbrrn chains that. when releasedfiom the ccll plasntii mernblane. areof variablelen-eth and thr-rs polydispersity.Despitethe sirnplicityof the HA primary structure.this linear polvelectrolyteadoptscorn- G H O S HA N D G U I D O L I N A N2 l- rLl G1 B N1 CHr O=C' CH.OH "Ho\\--o LoÇ_è:_-o N H- ^ , , y-F1.. o- - r , "ta", H G2 N2 Gr N1 F i g 1 . S t r u c t u r eo f H A i n ( A ) d i m e t h y ls u l f o x i d ea n d ( B ) i n a q u e o u sd i m e t h y ls u l f o x i d ea s d e t e r m i n e d b y p r o t o n N M R s p e c t r o s c o p ys h o w i n g t h e s u g g e s t e dh y d r o g e nb o n d i n g b e t w e e n t h e c a r b o x y la n d a c e t a m i d og r o u p s a n d r i n g o x y g e n a n d h y d r o x y l g r o u p s i n t h e r e s p e c t i v eg l u c u r o n y l( G . , ,G r ) a n d N - a c e t y l g l u c o s a m i n(eN l , N 2 ) r i n g s . I n t h e a q u e o u s e n v i r o n m e n t ,( B ) s t r u c t u r e sw i t h h y d r o g e n b o n d e d w a t e r b r i d g e s b e t w e e n t h e f u n c t i o n a lg r o u p s a r e p r o p o s e d .P a n e l ( C ) s h o w s a m o l e c u l a r m o d e l o f a s e g m e n to f t h e H A m o l e c u l ew i t h t h e h y d r o g e nb o n d s l o c k e di n p o s i t i o n sa s i n d i c a t e di n ( A ) .U n d e rt h e s e c o n d i t i o n s ,8 C H g r o u p s( s h o w n w i t h a c r o s s )b e c o m ea l i g n e dc o n f e r r i n gr e g i o n so f h y d r o p h o b i cc h a r a c t e rT. h e s eh y d r o p h o b i cr e g i o n sa r e r e p e a t e da l o n g t h e H A c h a i n a n d a r e c o n s i d e r e d t o p a r t i c i p a t ei n i n t r a - c h a i ni n t e r a c t i o n sa n d b i n d i n gt o p h o s p h o l i p i d sA. d a p t e df r o m S c o t t ( 1 2 ) . plex confbrmationsin solution.which engenclelit with diversebiolo-eicproperties. Within the joint cavity. HA moleculesare predorninatelysynthesizedby the type B synovial cells. These cells elaboratea polydispersecl HA populationwith MWs within the ran-reof 2 x 1 0 " - 1 0x 1 0 " D a . t h e s i z ed e p e n d i n -orn t h ei o i n t l o c a t i o na n d s p e c i e s( 1 , 2 . 1 1 )F. u r t h e n n c l r H e .A r s producedin largequantities.which encoura-res the fbrmationof extensir,'e macromolecular entanglc- HYALURONAN THERAPY IN OSTEOARTHRITIS INTRA-ARTICULAR 13 mentsand networksthat confèr unusualstifïness tied high or Iou' MW HA preparationswith the phospholipid. clipahnitoyl-D.L-phosphaticlvlchoto SF as mentionedpreviouslv. and viscoelasticitl, line. the proporticlnof flexible chain segmentsrn Although the ring orientationsadoptedby' the HA HA relativeto stifl' segmentscould be increased chains in solution are lar-uely'-eovernedby' the ( 2 2 t . A d d i t i o n a ls t u d i e ss h o w e dt h a t h i g h l y p u l i stericrestrictions to their rotationaboutthe various gly'cosidic f i e d H A c o u l db i n c lt o a v a r i e t yo 1 ' p h o s p h o l i p i d s . linkages.the hydrogenbondingbetrn,een functional -groupson the rings is an impoltanl including the pnrinllarlrnatorvplateletactivating liictor (2 I -23). determinantof HA conlirrmation.This uas shor"'n of HA. palticuThesernolecularcharacteristics bv rneansof proton nuclearnragneticresonilnce (NMR) spectroscop)'. r'u'ith MW r.r'hichshou,ecl clecreasing lalll the lossof chainrigiclit-vthe prescncc o1'hydrogen-boncling betnieenthe glr"rculonr I caro r i n t e r a c t i o nu i t h p h o s p h o l i p i d sh. a v e i r n p o r s ith respecto its boxyl group anclthe adjacentacetanrickr h1'drogen t a n t p h l , s i o k r g i ci n r p l i c a t i o n w o 1 ' t h e N - a c c t r ' l h e x o s u r t . r i nrt' 'i n g ( r i r r \ \ i r t c r ' inlrusn r o v i n lm e c h a n i s notl a c t i o ni n o s t e o a r t h r i t i s (o,\) b l i d - s e so ) f H A i n a q u e o u sc l i n r e t hI r s u l t i r r i c l c s o l u t i o n s( l 2 - 1 . + () F i g I i . l ' h e a d d i t i o n r l . u r r i c rt r r RATIONALE F O RT H E U S E O F I A H A I N O A r i n g r o t a t i o ni m p o s e cbl r t h c s cb i l a t e r l lh r c l l o s c n blidges favors a confixniation lirr H,\ riherehr . l o i n ts p a c en u r r ( ) \i \n g ( c i r u s c bt ly l i b r i l l a t i o na n c l I o s so 1 ' c a r t i l a s es) .c l e r o s i sa.n c ls u b c h o n d l ablo n e e a c h d i s a c c h a r i duc n i t a l o n g t h e c h a i n i s n r a i n br osteophytosis at the tained at 180' to the next. conl'erlin-sa l-lirld rernodelingaccornpaniccl joint margins are consiclered the cardinal racliohelical synlnretr)'.Significantlr'.this conlirlmation also exposeson alternatesideso1'thehelix repcatl o g i c s i g n so f O A . H o v u e v e ri .t - r e n e r a l l yi s a c in-9clustelsof 8 contiguousring C anclH atonrs also coexists cepted that sl,novial inUanttnatiot't r.'u'ith and is probably'cl'ivingthe that were consiclered to representlociitionso1'hr'thesepatholo-sies d l o p h o b i c i n( F i g l ) . M o l e c r - r l an r o c l c l i nagn r lc n c l i n i c a l l ra c t i v ec l i s e l s.eT h e S F l r o n rO A p a t i e n t s t v e l so f i n l l u n t n r a t o rtvr e c l t a e r g l ' c a l c L r l a t i o ni nsd i c a t e ct hl a t I H A c l r a r n :r ' u n c o n t a i n ss i g n i t i c l r nl e t rl'l l r c t i rl r t i o t t n i n u a n t i p a r a l l etl o c u c l r o t h e r c o u l c l u n t l e l l r r t o r . u n t i t r t h c lr l a l k c l s o l i l r . t r . t t t tcr e i n t e r a c t i o nuss i n St h c s cI r rr l r . r r t l - 1 l f i r . l i n r l r ù r ' u n rC ' - r a e ï - t e c t i vien t e r c h a i n ' ec t i rc l t r o t ei n l c ' re l s a r e p h o b i cr e g i t t n s( 1 . 11. . 5 e l e ru t e crl l r ) r . t . T h i s s t r g g:et i ( ) l t\ \ i t \ c ( ) r t \ tiueral ilc \ o 1 's r n o v i a l t t t e r t . t s i s t e n t w i t h e a l l i e r v i s c o e l a s t i cn r c i r s r . u ' c n r c n t \ . I r . t t r t . t u n o l . t i : t o l o g N M R t ' e l a x a t i o nt e c h n i q u c s .r o t a l r ' - s h u r k r r i i n g blanc biopsr s1'rccinrcns ll'onrO,\ piltientsshouecl prcse lvnielectron microscopy. and computcr nroclclin!r. thc nce ol' T helperanclT rul"rprc-ssion which had inclicatedthat HA could undergointll.rphocvtes. B l-vnrphocvtes. nracrophage-exan(l p r e s s i n lH L A - D B i n l y r n p h o i cl li r l l i c l c s .w h e l e a s c h a i n a n c li n t e l c h a i na s s o c i a t i o n(s1 6 - 1 9 ) .H o u , eVel'.the chenricalnatureof theseinteractions and clifTusecellular infiltratecontaininggranulocvtes. the relativeorientationo1'theacljacent T and B lyrnphocylcsand HLA-DR positivernacchainshatl nol beenresolved. lophagesu'ere identitieclin many of the biol.rsy' It was proposedthat the interchainduplcx cous p e c i n t e nesx a r t r i n e1d- 1 0 . 3) .1U s i n - ei n s i t uh v b r i c l plin-ls betweenthesL'h1-'drophobic pttches cor-rld ization and biotin labeleclriboprobes.Sn.ritlrct iil ( 3 2) c o n f i r m e dt h e p l e s c n c co f c y t o k i n e s( i n t e r l c u accountfor many'o1'lheknown phvsicalpfoperttes ( 2 ( ) . l l ) . o f H A . s n c ha s i t s L r n u s u a lhl yi g h s t i f f n e s s k i n [ L l - l r r a n c lB . t u n r o rn e c r o s i sl a c t o r-' a ) a n c l Furthermore. thesecontiguousCH regionsofl'clccl I L - I r e c e p t o ru n t a g o n i s (t l L - I r a ) . i n s y n o v i a l possiblesitestbr aclditionirlIryclrophobic intemcmembranebiopsl specinrensfl'ori'rOA patients. tions. such as with cell membranes.anclbiologi.tMoreover.the leiels of thescproinflarnmatol'1, call1,in.rportant lipicls(21,).Experirnentalsuppolt lt'rkinescorlclatcdwith the radiologicgraclingof fbr such complex tbrmationsu'as pluvided b1' a thatthe cytokinrdiseaseseveritl,.It wasconclr-rdecl s t u d yu s i n g' H - N M R s p e c t r o s c o p( 2) ,2 ) .T h e c h a i n pnrfilesanclthe cleclinein o1'lL-I ra actir.'ity "vere f l e x i b i l i t y( s t i f f n e s so; 1 ' av a r i e t yo 1 ' H A sw a s l r e a n o t d i s s i n r i l atlo t h a t s e e ni n r h e u m a t o i da r t h r i t i s suredfiom the spin-spinrelaxationtirneso1'thcir' synoviur.n but was cl1'alesserintensitv.Thesedata acetamiclo were consistentwith the report of Wagner et al -qfoupprotons.The stitfnesso1'highly (33) who useclPCR to quantitatecytokineslevels purified HA preparationsincreasedas the MW increased;however. bl sonicatirr-u highlv pulii n s y n o v i a lb i o p s y s p e c i m e n sf r o r n O A j o i n t s . 14 They are also consistent with the stucly by Roir,'ainen et al (34) and Marok et al (3-5).who leportedthe increasedexpressionof oncoprotcins and proinflarnmatory mediatornuclearfactortranscriptionfàctorsin OA synovialcells. The presence of prointlamrnatory cytokines.free radicalsand proteinasesin OA synoviu can ildl'erselyaftect the rnetabolisr.n of the lining type B fibloblasts,leiidingto the biosynthesis ol HA w,itlr abnonnalMW. as has becn shown b1'analysisclf S F f r o m p a t h o l o g ijco i n t s( - 5 , I1. 3 6 . 3 7) . I n a d c l i r i o n . HA alsornaybe depolyrrrelized bv oxlgen-clerilecl fl'eeradicals(38-.10)and intlacellularlrbr hValut'ctniclases. iind other -tlycosiclascs tÏrnt svrtoritrcytesand ler-rkocytes in the sr nor iLrr.r.r t-1l .-11r. T h e c l e c l i n ei n H A r n o l c c u l asr i z t 'c o u p l e dn i t h i t s d i l u t i o n b y i n t i l t r a t i o no l p l u s n l r l l u i d a n d p r o t e i n s( c a u s e db r i n c r e a s e sdr n o ri a l n t e r l b l a n c p e l n r e a b i l i )t lr e d u c ct h e r h e o l o g i c al lt r o p c l t i e so f S F -l i o n r O A . j o i n t st - 5 . 1 1 . 3 6 . 3 7 . -A1s0 )a. c o n s c qLlcnce. it n asconiendedthatcaltila-rcattlitionand subchonclral bone rentoclclingwas enhancedcontributingto progressionof OA and clinical syrrrptonts. On the basisof thc leciucecl rheologicalpropert i e s o f t h e H A i n O A . j o i n t f i u i c l .B u l a z sa n c l Denlinger(;13)anclothers(-1-1.-15) inrrorlrrccrl rhe c o n c e pot f v i s c o s u p p l e n t L ' n t l r ti inonn .h i eh t h c u t r n o l m a l S F l l u i d w a s a s p i r a t e cf rl o t n t h c i r l f c e t ù r l . j o i n t .t h e n r e p l a c e cul i t h p u r i t r e dh i g h \ l \ \ H . \ . T h c r a t i o n a l ef b r t h e u s e o f t h i s p n r c c d u r ei n t h e treatnrentcll'OA was to l'estoreol supltlentent SF viscoelasticitw y .h i c l t i v o u l d i n t p n r v e. j o i n rl i r n c tiOnalitl and consecluenllv decreases)'lilpt()nt\. Although clinical str.rdies undertakent() tcst thc Balazs h1'pothesisr,,,eresupportivcin telnt' o1' l e l i e f o f O A s v r n p t o t l s( . 1 3 - 4 8 )i .t w a s o b s e r r c c l that the clinical oLltcorresubtainedb1' this approach also coLrldbe achievedlvith HAs u ith MWs less than the HA in SF aspiratedfiorn rhc o i n t . F u l t h e l n r o r et h. e c l i n i c a cl l f l c t i r e c l e t è c t i vj e nessof the therapl'rvasol'tenin excessof serclal w e e k s o r e v e n t r - r o n t h su.' h i c h w a s i n c o l t s i \ t e n t lvith the kno'"vnrate of clealanceof HA liorrr s y n o v i ajlo i n t s . I nj e c t i o no f r a d i o l a b e l eHd A i n t o k n e ej o i n t s o f norrtral rabbits afforded tvera-qehalf-lives lbr c l e a r a n coef l c s st h a n2 - 1h o u l s( - 1 9 - . t l tI.n a s h e e p rnodelof arthritisinclucedby IA injectiono1'rvpcIl collagen,pharrnokineticstudiesshoweclthat the metabolichalÈlitè of lA injectcclradiolabeled HA G H O S HA N D G U I D O L I N cleclincdfhrrr 2l hoursbetbreinductionof arthlitis to a lrean valueof I 1.5hoursafier lA in jectionof the antigen(-52).Fulthen.norc. analysisof the clata indicatedthat the meantl'actionalturno\rerfate of racliolabeled HA injectedinto the inflamedjornts uas alrrost clor-rble that in the noninflamedjoints (3.-5%/hr 6.3c,4 llt). This increiisedturno.n'erof racliolabcled HA in the inflar.necl .jointswas accolnpaniedbv accurnr.rlation of its rnetabolite. tl'itiatecl 'uruter'. in lvmph and trlood. It is clcur lhrnr theserellortsthat the obsened I u n g - t e l ncr l i n i c l l b c n c l i t sa l ' f b r d e db 1 'I A a d n t i n istlutronof HA cannotbe fully accontrrrcldatecl bv t h e e o n c e pot f v i s c o s u p p l e m c n t a t i H o no.w e i . ' c ri 'f. tht-HA Lrsccl firr IA therapyin OA u'asnot nterell' l c t i n s a s a v i s c o e l a s t iS c F sLrpplemen b tu t , " r , a s crhibiting usefulphamracolociceftèctson thc uncler'lying pathologicsresponsible for the svntptonrs. then its lon-g-term clinical efficacr nricht be fationalized. A r c v i e v uo' f t h e e \ t c n s i \c l i t e r a t u r eo n H A shovnecl that it dicl crhibit ir spectrLulof phalnrac o l o s i ca c t i ri t i c s .n r a n ro l r rh i c hc o L r l c. rlc c o u nf tb r its abilitr to leducc-pain ancl inflarnntationancl c c t i ii t v i n O A . M o r e c l l , e r . l . r o r s i b lnr r o c l i l rc l i s c u . a t h c s el u b o r a t o r sr t r r c l i ei n: d i c a t e ct hi a tt h e b i o l o g i c a c t i \ i t i e so l ' H A p r e p a l a t i o nns' a s d e p e n d e nnt o t o n l v o n t l ' r cc o n c e n t r a t i o nuss e db L r ta l s o o n t h e i r ' \IW, P H A R M A C O L O G IBCA S I SF O R T H E USEOF HA IN OA It is nou' wiclel-racccl)tcclthat HA bincls to l e t e r n t i n u nl C s p c c i l i cr e c e p t o r(sc l u s t c d t D l - 1 - 1i n. t f a c e l h l l aar d h c s i o nn t o l e c u l eJ I C A \ , l1- I . r e c e p t o r l i r r h v a l r - r l o n u t e - n t c c ln ilto e t il l i n l R H A M M I I t h a t are e\pressecl bv a u rrlelan-rreol cclls. incluclin,g t h o s ei m p l i c a t e ci nl t h c p a t h o k r g yo f O A ( c g . r n llanrnratolycells.sr n()\iocytcs.ancichonclrocvtes) l - 5 3 - 6 6 )I .t a l s os t f o n - l l livn t c l a c t sr v i t ha v a l i e t yo f p l o t e i n s( h y ' a l a t l l r c r i nssu) c. ha sl i n k p l o t e i n w . hich is part tl1' a.g.grecan lncl r crsican cornplexe s in cartila.ue(67) ancl firnns pericellular ntatliccs ntouncllnany tvpùs of cells. including chonclroc 1 ' t e s( 6 3) . l-hc finclin-uof speciliccell rcceptofsfor HA. ncltiiblyCD4;1.sLrpporta pharntacolo-ric nrechanisrn of action filr this GAG in OA. and because thescleceptorsare wiclelyclistributed on the surf acesof manytypesof cells.it alsoaccoLlnts fbl the cliversityol' its efIècts. 15 INTRA-ARTICULA HR YALURONAN T H E R A P YI N O S T E O A R T H R I T I S The binding of HA to CD:l:l anclRHAMM and their variousisofbrmshas beenreportedto trig-uer' a varietyof intlacellulnrsignalcvents.suchls the protein phosphorylaticlncascades.cl"tokine rel e a s e .a n d s t i m u l a t i o no f c e l l c v c l e p n r t e i n s( 6 8 7 0 ) . M a n y o f t h e s ec e l l u l a rp r o c e s s ehsa v e b e e n l ill not be clisr e r . ' i e w eedl s e w h e l e( 6 3 . 7 1 ) a n c w cussedin detail hcre.Nevertheless, it is impoilant to note that. in -leneral.tlre consecluencc of'these receptorinteractionsby HA is to stinrulatetnllrsduction anclothcr si-cnalin-g pathwavsthat nrocluprinralill late cell fnnctionalactivitiesmanitèstecl b y c e l l n r i g r a t i o np. l o l i f è r ' a t i o na.n d e n d o c r t o s r r . Fi-eure2 sho'"vs r.rscherriatic reprcscntation o1'sonrc o f t h c H A - C D . ! l s i g n a l i n gp l t h \ \ ' i r ) st h u t h a r e b c c ni d e n t i l l c da s r c p o l t e cbl r l - e t 'a n dS l r i c c rt l I t . S t u d i e so n t h e e f ï è c t so l ' H . \ s o n C D - 1 -c1c l l u l r r r ' signalin-lhave shovn'n that thc lesultscun l-rcconon the sizc-of thc HA moletladictorvclependin-u c u l e sr . r s c cFl .o r i n s t l n c c .l o r i M W - H A s ( 0 . 2 8 x 1 0 6D a a n c l0 . - 1 7x l 0 ( ' D a ) r v e r es h o w nt o p r o motechenrokinegenccxprcssionby macropha-ues. *€,t{*f{* whereasa comrnercialpreparationof HA with an M W o f 6 . 1 x l 0 ô D a d i d n o t ( 7 2 ) .T h e s ec l a t al e d O h k a w a r ae t a l ( 7 2 ) t o s u g g e stth a t l o w M W H A tl'agrrrcntsgenefateddr.rring.joint inllammation ma)' perpetLlate this processby enhancingexpression of -ueneproductsby residentmacrophages. also ma1,ploThe srrallcr MW HA prepat'ittions nrotc r.rsciirlcellLrlareffects.Ohkawaraet al (72) slrorieclthat an HA preparationof MW : 0.2 x 1 0 " D a \ \ ' a s r n o l ' ec l ' l c c t iei i n n r a i r t t u i n i ntgh e s u r ri v l l o f b l o o cel o s i n o p h i ltsh a nH A w i t h a n M W o l . l X 1 0 ( ' - 6x 1 0 6 D a . o h k a w a r ae t a l ( 7 1 ) proltosgllthat thc protccti\c-cl'tèctaffordedbv the l o r rc r '\ l \ \ ' H A o n t h e s ec c l l sr i a s n r e c l i l t evcila t h e i n c r c l s c r lc r p r c s s i o no l ' g r a r t u l o ct er t n a c t ' o p h a t c r I' ) - l - la c t vi a t i o l r . c o l i r r r-rr t in r ul l t i n g f u c t o rl-r l ' t c C T h c n r c - e h u n i s nr er ss l - r o n s i bl ilrcr t h e s ec o n t r a s t cell inu \l\\ -rlcpcn(lL'nt ef fect\ of HAs on clil'tèrent but may. in part. tvpes are still poorlr unclclstoocl be relateclto thc clLlstcrin-e and crcss-linkingof It ts CD:l;l receptorsolr their plasmamet.nbrane. knoi.vnthat bindin-sof HA to the CD.l.l link nrocl- "-**"*.*rfe -'- | **g.+**.# El* ;4:tm'fp *fT1 ^ qEÈF=-:1--:'Èsç- @el ?:æ v ô9 ,-.'^^@ \@v_, c T@, @9;;; 'ttll - Fig 2. Diagrammatic representation of the CD44 cell surface receptors showing their possible i n t r a c e l l u l a sr i g n a l i n gp a t h w a y s ,w h i c h c a n b e a c t i v a t e db y H A . T h e 4 s i g n a l i n gc a s c a d e si n v o l v i n g CD44 have been identified. Pathway (A) requires activation of the src-relatedtyrosine kinases,(B) heterodimerizationof CD44- erb 82 may activate a MAP kinase (MAPK) cascade,(C) the nuclear transcription factor xB (NF-rÊ) may be activated through HA interaction with CD44 and a protein kinaseC (PKC()dependentcascade,and (D) activationof GTPasesby HA-CD44interactioncan lead to reorganizationof the actin cytoskeleton.Modified from Lee and Spicer (71). '16 G H O S HA N D G U I D O L I N ule rrses discrete hexasaccharicleelements along t h e G A G c h a i n ( 7 3 ) . T h e H A o l i - e o m e r so i 2 0 - 3 0 sugar units can therefbre interiict with rrure than I CD4-l receptor. Nkrreo'uer'.these HA chain t'r'agInents can displace macrornolecular HA frutm its m L r l t i p l eb i n d i n g s i t e s( 7 3 ) . F o r a c e l l u l a r f' e s p o n s e to ensue atter HA binding. the fitrrlation of a stable receptor complex involving c(x)perati\e interact i o n s o f ' s e v c r a lC D J - 1 r e c e p t o r s( c l u s t c r i n g )w i t h a single HA molccular strancl lnr\ ( 6 3 . 7 3 - 7 .)5. bc requirecl I t i s p o s s i b l e . b u t a s Y c t L l l i p f o Y c l r t. h a t H A p r e p a r a t i o n sw i t h i n a s p e c i l i c r i z e r a n g e c o u l c l provoke a pattern of CD-t-l clusteling and cross- clinical practice: an example is Hylan G-F 10. which is a rnixture of a hi-uhMW HA with a cross-linked HA prepalation. the curnbinatron hal'ing an MW range of 6 x 10"-23 X 10" Da. Hou'er,'er.rnany of the HA preparations currentlv u s e d t o t r e a t C ) A h a r . eM W s i n t h e o r d e r o f 1 . 0 X l0(' Da or less ancl nlost ol'these are lcportecl to be cfficacior,rs.Ale r.'n'e to assunle that these riLrious H A p l e p a r a t i o n sa r e c l i r . r i c l l l ve c l u i v a l e not r i s M W reallv an irnpoltlLntlctenrinant ol'clinical efteetive ness'.t l i n k i n g o n b i n d i n g . u ' h i c h t h e n r r i g g e r sa 1 1i l t t r a c e l lLrlal si-enal.whercas the lar:Jcl'H,\ rnolecr-rlcs nrav Notwithstancling the irnportance of these cprcstirrns.satisfactorvanswershave not been generatecl b y c l i n i c a l i n r . e s t i g a t i o n sI .t m i g h t b e a r g r - r e tdh a t . e v e n i f w ' e l l - c o n t r o l l e db l i n c l e ccl o m p a r a t i v cc l i n i rvere undertaken u'ith HAs of difterent cul stLrclies o c c L r p vt h e s e r r L r l t i p l eC D - 1 - 1l i n k i n s s r t c sh u t p r e V e n t r e c e p t o | c r o s s l i n k r n sa n r l u c c l l u l l r r r e u c t l o l t ( 7 6 ) . B e c a L r steh e H . \ l l r e \ e l t ti n n o r n t u le( ) n l t ù L t iù\ t i s s u e si s g e n e t t l l r o l h i g h \ l \ \ . r t u o u l t l . c c n t t r r \ 1 W s . i t i s d o u b t f u l t h a t t h e n r e t h o c l sc u r r e n t l r r r r u i i u b l c[ ( ) r \ s c s s i ] a t i e n tr e \ p ( ) r ) \ et o t h e s e p a l ' a t c H . \ t f ù i r t r ) r c n t\s 0 t r l t l l - r es c n s r t nc e n r l r - r gtho d e t e c t \ n l i t l I r l l l t c r c r ) r ' ci\n e l n t i e l rcl l l i c r r e r 'T. h e p r o b l e n t ntake biolo!Iic:ertse tirl it not lr) uuntilluuLl\l\ s t i m u l a t ea n a c t i r e r e \ l ) ( ) n \ c t h l l t l t c e e l l : i t . u r ' r o u n c l sS . tuclieb s y S n r i t ha n d ( i h o : h t 7 7 r i n 1 9 8 7 t o r r l t l l r c l L r r t l t c re. o n t | o r r n t l c t lh , r t h e s t r o n g p l a e c b o c l f c e t l ù [ r ( ) r ' t cl (i rl f L \ t | c i i t l l l c n t (s7 9 ) . a s w e l l l u st h e p r e s c n t l i n r i t u t i o n r o t n o l r i n ra s i v e m e t h o c l s o f a s s e s s r r .\ttgn l c t u l a l ( o r r l i : c l l ' c ) n t o t l i f i c a t i o ni n O r \ a n c l t h e p a t i c n t ' s I c \ p ( ) n \ a t o t l I L r gt f e a t n l e n t s o \ e r a p c l ' i o d o f t i r r r e s u t l i r ' r c l r tt ( ) ( l c t c c t \ r . l c h o n t h e i n v i t r o e f t e c t so f H A s u r t h a u i d e l a n - l e o f M W s u n h u n r a n s y n o i , i a l t i b r o b l a s t sb i o s v n t h c s r s of HA provided erperimental er,iclenccto support such an interpretation. Hon'ever. thc situation is further cornplicated b1, the |cccnt obser.n,ation that HA can feaclil.n'enter cells bv an unusual endocl'tic route un(l interact w i t h s p e c i f i ci n t r a c e l l u l a rp f o t e i n s( 7 8 ) . F o u l i n t r u c e l l u l a rH A b i n c l i n gp r c t t e i n (sr e c e p t o r s ) h l r eb e e r r d e s c r i b e d( 6 3 . 7I ) . O n e o f t h e s e .R H A \ l \ l s i s n o r m a l l v a s s o c i a t e cwl i t h t h e a c t i n c \ t ( ) s k c l r ' l o nu n c l n r i c r o t u b L l l e sr ., ,h c r e i t c o l o c a l i z e su i t h e r k I p r o t e i n i i n c l M E K I u n c i n r o d u l a t e st h e i r s i g n a l i n g . Significantll'.the bincling domain fitr elk I on RHAMM is the sarneas tor HA. sug-sesring rhe possibilitv that the HA ntay cornpete lirr the erk I b i n c l i n - sc i t e w i t h i n t h e c e l l ( 7 1 ) . stnlcturûl chan-!es. Bv contrlst. in r,itromodels unrl uninlrl nrotlels o f O A a l l o r , i.' j o i n t t i s s L r e tso b c u r r u l rz c r l r l i r c c t l r ' . tusins r alidatetl rrtethoclsrrt ils:ùssllent untl oftèr' o t h e r a d v a n t a g e sf i r r c o n r p l r i n L t l t c r r c t i ri t r e s o f r l i f f è r e n t c l r u g su n c l e rt l r c : u n t c c r p c r i n r c n t u l c o r r r l i t i o n s . T h e s e r n o c l c l r l u r rc h e c r t r l r r l c l v u s e c lt o r - \ ' a l u a t et h e l e l a t i r c P i r u r n r u c o l o u i cet f è c t s o f H A o l ' d i f t è r ' e n tM W a n c l h l \ ù , ' c l r c r l t c r lu s e f u l i n f i r r ' t t t t t t i o (t rt l l l h i \ i r t t | r ' t l l r tlt,t' l r i t . F o l t h e a b o v c r e i i s o n : . r i e h u r c c o n f i n e c lt l i i s l c r i e l v t o i n r i t r o a n t l i l n i l l r i r l i n r e s t i g a t i o n st h a t h a v c e v a l u a t e c lt h c P l l u ' r n a c o l o u i c a c t r v i t i e s o f H A s o f c l i t f e r c n t \ l \ \ . W h e r e p o s s i b l e .u e a l s c r D e s p i t ee r i s t i n - se \ t e n s i v e l i t e f a t u f et h u t c l e a r l v h a s s h o w n m o l e c u l a rs i z e c h a r a c t e l i s t i c o sf HA ale have includecl the lr-u fcports clescribin.ulabolat o r y s t u d i c so n . j o i n t t i s s u e b i o p s y , s p r ' c i n r e nosr i n r p o r t a n t d e t e r r n i n a n t so f i t s b i o l o g i c a c t i r i t v . there has been linritecl recognition of this fact in clinical practice. It generalll, has been acceptecl fluicls taken fnrrl OA patients before ancl afier a c o u r s c u t l A t r e a t n r e n tw i t h t h i s a g e n t . that the higher MW prc-paratior.rs wor-rldbe superior to HAs of lowcr MW because the firrnter wor-rlcl better fulfill the requirernents fbr ef'Tectiver.iscosLlpplementationas clescribeclby Balazs and Denlinger (.13)anclother investigators(.1,+-;18 ). Indeecl. E F F E C T SO F H A O N I N F L A M M A T O R Y C E L L S AND IMMUNOMODULATION IN VITRO An earlf in vitro stuclybv Forresterand Wilkins o n ( 8 0 ) s h o r , i e dt h a t H A o f 0 . 7 x 1 0 6 D a M W inhibited leLrkocvtcntigration. chemotaxis. unclad- H A s w i t h h i g h M W a r e i n c f e a s i n g l yb e i n g u s e c li n hesion in a concentlution de-penclent manner. For- I N T R A - A R T I C U L AH RY A L U R O N A NT H E R A P YI N O S T E O A R T H R I T I S 40 rester.ind Wilkinson (tlO)showeda leductionon bindingof chemotiicticfhctorsto thecell surf-ace in i30 *..l the plesenceof HA. Neitl'reldextransullatc nur f i-Tll chondroitinsulfirtchad any' el1ècton neutrophil miglirtion.Theseobservalionswere confirrrrccl bl Partsce h t a l ( 8 1) w h o s u g g e s r erchla rh i g hM W - H A i n s v n o v i a jl o i n t s p r o v i c l e da p h v s i c a lb a r r i e rt o e n t l ' vo 1 ' p o l y m o r p h o n u c l e( aPrM N ) c e l l si n t o t h e c a v i t l. U s i n _H r A o f u n c l i s c l o s eMdW . P i s k oe t a l Hyaluronan concentration (mg/ml) (82) nrade the observationthat. at norntal.joint Fig 3. Inhibitory effectsof HA of different MWs concentrations of :1 rn-e/rnL.HA inhibitedneutloa n d c o n c e n t r a t i o n so n a c t i v a t e d n e u t r o p h i l phil phagocytosis. Hclwcver.at a concentration of m e d i a t e dc a r t i l a g ed e g r a d a t i o n .N C = n e g a t i v e I rng/nrL. as occurs in inllantecl.joints.no sLrch c o n t r o l ,p Q = p o s i t i v ec o n t r o l ( w i t h o u t H A ) . ( : ) ef-fectwas observed.Stuclicshv Tantot()ct ll H A - M W 0 . 2 8 x 1 0 6D a , ( - ) H A - M W 0 . 9 5 x 1 0 6 ( 8 3 . 8 . 1e ) x a n r i n e dt h e i n v i t r o c f ï c c t : o l . l H . \ D a . ( w ) H A - M W 2 . 0 x 1 0 6D a . T h e d a t a s h o w s p r e p a r a t i o nwsi t h M W s o f 0 . 3 x l 0 " l ) r . 0 f l i 1 0 " t h a t t h e H A p r e p a r a t i o nw i t h a n M W o l 2 . 0 x D a . a n d 1 . 9 X 1 0 " D a o n p h l g o c r t o : r sc.l t ù n r o 1 0 6D a w a s s i g n i f i c a n t l ym o r e e f f e c t i v ea t r e d u c gc.n-ilclir taris. and procluctionol' orr ctl Îl't-.clutli, i n g t h e l o s so f g l y c o s a m i n o g l y c a n( sG A G s lf r o m cals bv stil'nulrtL-(l P\l\ lcLrkocrtc-s lncl ntilctl)c a r t i l a g et h a n H A s o f l o w e r M W . * * P < . 0 1 ; p h a g e sT. h e h i g h \ l \ \ ' H , \ p f e p a r a t r o(n1 . 9 X l 0 ( ' * * * P < . 0 0 1 .M o d i f i e df r o m T o b e t t o e t a l { 8 6 } . D a ) u a s t h e l l o s t c . f t è c t i vien h i b i t o ro f c h e n t o t a x r s a n d . t o a l c s s e re x t e n t .p h a g c l c v t ifcu n c t i o n s A . t concentration\up to 2 rng/ml. none of the HAs str-rdied inlluencedthe ploduction of oxygen-clelvmphocyteprolilèration(87). Tu,o mechanisnts rivccltl'eeradicalswhen cellsu,crestintulateduith fbr HA effèctswere proposecl by' tlieseinvestiglieither serum opsonizeclzlntosan or litrmvl-rnettors:one bl, reducingcell intefactions andthc other leu-phepeptide.It rn,as ploposeclthatthe effècrsol' by' the binding o1'rnilogenenhancingfnctors lcH A o n t h e i i c t i v a t e cnle L r t r r r p l tui lcsl c r i a i n t e r a c lcaseclby the stintulatedlymphocvtes(87). tion vuiththeir CI)-1-1 ecll recr.1'rrot's. The rnodulatingeffèctsof HA on inflantmaturv D u r i n - gt h e i n l l u n r n r i r t o tp' \r o e c \ \ .P \ l \ l r . L t k o e c l l a c t i v i t i e sa l s o u ' a s s u p p o f l c db v a n i n v i t r o c y t c s n r e c l i a tbeo t h en z v n t r l i cu n ( l o r i r l r r t icr 1 r 're. ' t u r l r ' o r " lru h b i t n e u t r o p h ial c l h c : i o na n c la g g l e g u r a d i c a lr e l l c t t o n sl.e a d i n gt o t i s \ t - t cr l u n l r g c . ' l - h r ' t i o n . I n h i b i t i o n\ \ a s c k r s c - r l c p c n d eanbt o re 1 0 0 H A e x h i b i t e dM \ \ ' - d e p c n c i e fnet a c r i v e o \ \ g c n\ l ) ù pr/nrl-rrnrH l , \ s n i t h N I \ \ ' s. . I x 1 0 " D a r i e l e c i e s s c a v e n g i n -agc t i v i t v t h e l e b vp r o t e c t i n u. j o i n t ilLletr\c (liN). t i s s u e st i o m o x i d a t i v ed a n t a s e( 8 . 5 )I.n t h i s r e : . : l r r t l . EFFECTS OF HA ON SYNOVIAL PrestitrnclScott(8-5)r'eportecl lhut an HA plePuluF I B R O B L A S TIS N VITRO tion with an MW ol' 1.2 X 10" l)a \\'a\ ntorc ctfectivethtrnHAs of 0. 176 X l0(' Da anclO.(r(rfi x Hunran slnor ial fibroblastsderiveclfronr OA I0(' Da MWs in protecting tenclontibroblasts culturedwith HAs respondccl bi, up.jointsvu'hen againstoxidativeclantage. Theseinvesti-gators susregulatin-uor down-regulatin-u cnclogenousHA svnthesis.clependingon the media concentratictn -gestedthat HA forrned a meshworkaroutrclthe cells u'hich was anchoredto their HA receptors (77). a n d t h e M W o f t h e e x o s e n o u sH A a c l c l e d therebvreducin-s the et'fectiveinteractionbetu'een S t i r n u l a t i oon1 ' H As y n t h e s irs' , , apsl o d u c e db y H A s the radicalgeneratin-s speciesand the cell mcnr$ i t h M W s > 0 . - 5 X 1 0 ( 'D a a t c o n c e n t r a t i o nbse brane.Sirnilar conclusiorrsvu'ereleachedb1' Totueen l0 pgllnl and -100pg/ntl-. Hou'ever.lower betto et al (tl6). who desclibecla colrclationbeMW-HA preparations had n'rinirrialeltèct. ercept tween inl.ribitionof ueutrophilrnediatecl cartilage at highconcentration wsh e n i n h i b i t i o no f H A s v n damageand HA MW and conccntrationin vitro t h e s i sw a s o b s e n ' e dA. n i n t r i g L r i ntgi n d i n gi n t h i s (Fig 3). An HA plepalntionr,"ithan avera-se MW stucll'lvaq that the cell responseappealeclto deof 0.92 X 106Da was rnoreetI-ectilethan a lower creaser.l'henHAs clf MW >3 X l0"-rl X l0'- Da M W - H A ( 0 . 1 1x 1 0 6D a ) a g a i n srtn i t o g e n - i n c | - r c e c i were used.The authorshy'pothesized that llA svnG i[ïffi 18 thesiswas mediateclby interacticlnof this GAG with surfacereceptors on thesetibroblasts thatonly promoteda si-rnalfol incleasecl synthesisby bindin-cto HA within a ccrtain molecularsize range (see the sectionon HA receptorsfbr further disc u s s i o no f t h i s p o i n t ) . Theseclatasuggestthat synoviiillype B cclls.the major sourceof svnovialHA. ntay be capablcof sensingtheir extlaccllularHA environnrentancl translatingsuchinfbrmationinto the expressionof gencs.rvhichleirdto the de novctsynthcsisof HA. This processrequiresactivationof the enzvrncHA svnthase.which is locatedat the inncr sulfaceof thc plasmamernbrane(89). O t h e r s t u d i se u ' i t h s v n o v i a l fi b r ' o b l a s t h sur.. shown that the releascof arachiclrniclcitl lnrl production i n. t P G E . )f n r n t p l . r o s c l fp r o s t a r l u n c l E p h o l i p i d sb 1 ' e c l L r i (n9c0 ) a n csl t i n r u l a t ehcLl r n l r nO . \ c e l l s u ' a s i n h i b i t e cbl l t h c p r e s e n c o el ' e r o s e n o u s HA. the eflbct again bein-rclepenclent on its conc e n t r a t i o na n c lM W ( 9 1 . 9 2 ) .H i g h M W - H A ( 2 ^ 10" Da) was the most potentpl'eparation but HAs w i t h M W b e r w e e n0 . 2 8 x 1 0 " - 0 . 9 8X l 0 . D a a l s o were active.particulallyat concentraticlns between 1 . 0t r n d2 . 0 m g / m l . Pelicellulartibrinoll'tic acti\ it\ ^ as tleterntinecl b y a s s e s s r . n eo nl ' t h e l e r e l so f u P A { u r i n i r l rp J u s r n i n o - u canc t i v a t o r )p. l a s n t i n o r : ci n t c t i v u t ( )i rn I t i t r i t o r - 1 . a n c lL t - P A R( u r i n a r r l t l a s n t i n o u cinr e l l \ l r t o t ' receptof)secretecl in cultule br hr.rrlanO.\ srnov i a l f i b l o b l a s t sw. a s i n h i b i t e cbl r t h e p r e r e n c eo f H A w i t h a n r e a nM W o f 0 . 9 x l 0 " D a ( t ) - l t .T h i s efTèctrlay have been ruecliated h1' thc inltibitoly cf-fects of HA on PGE. prociuction(93). Hor',cvcr. becauseHA also sLrppl'esses the prodLrctionof lL-lB by svnor.'iirlcells by acting on thc CD:l-l r e c e p t o r( 9 2 ) . a r e d u c t i o ni n t h e a c t i r i t v o f t h i s c y t o k i n ec a n n o tb e e x c l u d e d .[ L - l B L r p r c g L r l a t c s fibrinolyticactivitl'nsindicatedby increasecl u-PA and t-PA expression by chondrocytes anclslnovial fibroblasts(9,1).Fibrin depositionis a conin.rorr fèatureof SF derivedfrom rheurnatoid arthritisand O A j o i n t s( 9 - 5 ) . When synovial fibroblastsfiom human OA joints wereculturedin the presence of HA of MW of 0.9 x 10ôDa. secretionof uPA anclits inhibiror plasminogenactivatorinhibitor-1were decreased over a 48-hourperiod (93). This findin-cwils consistentwith a plevit'rusOA study fiom the sarre group using HA of the sameMW. which showecl that the declineirr theseSF tàctorscorrelatedwith G H O S HA N D G U I D O L I N a decreasein patientsymptoms2 weeks after lA administlation(96). Theseresultscontrastedwith sirnilarin vitro studiesthatevaluatedHAs of MWs o f I x l 0 ô D a . 0 . 5 x 1 0 6 a. n d0 . 0 6 - x5 l 0 ( ' D a o n thc cxprcssionof proinflarnmatorycytokine ancl chenrokinernessa-ge b1' chonclrocyte anclsynol'ial librclblastsll'onr OA .joinls.wl.rereno ef1èctwas s h o w n( 9 7 ) . EFFECTS O F H A O N C H O N D R O C Y T EASN D ARTICULAR CARTILAGE IN VITRO A d u l t r a b b i tu f t i c u l a fc h o n c l r o c v t ecsu l t u r e di n the plescrtcco1'a rcconrbirtant hurran intelleukin l l h l l t - l p a n c lH A o f N l \ \ ' b e t w e e n0 . 5 X l 0 ô D a - 1 . 0x l 0 ( ' D a r l e r c c a p a b l co l ' i n h i b i t i n gP G E , protlr.rction ir.t it concentrationnrilnncr'.however. tlrc hi-gherMW preparations uere the rnoreactive (9E). The rhlL- I B induceclproductionof superoxide anionfiee radicalby bovinechondrocvtes also was miti-uated by HA of MW 0.8 x 106Da (99). confirmingthat HA fiactions with MW < 1.0 x 106Da are capableof rr.roclulating the responseof articularchondrclcytes to inflammiitolymediators i n v i t r o .T h i s a n t i c y t o k i naec t i v i t yo f H A a l s ow a s s h o u ' nu ' i t h f c s p c c t o t h c l h l L - l B o r t u n t o rn e c l o sis luctor-rr nrecliatecl releaseo1' protco-ult,cans t i o n r t h e ù \ t l i l c c l l u l i u ' r l l t r i r o f i r n n i a t L r rrea b b i t c l t o t t t l t r r e r t et :l ( ) ( ) ) u n t l b o r i r t c c r p l a n t c u l t u r e s t l 0 l t . . \ l t l r o u g ht h e l en a sa n r a r k e cdle p e n d e n coyf t h i si n h i b i t i o n( ) nt h L r- ' c s p e - c t iHv A c concentrations Lrsccl. HAs ri ith \l\\ s rr ithin the ran-ccof 0.3 X 106 D a - 1 . 9 r l 0 ( ' I ) a a l l c x h i b i t e ds i m i l a r a c t i v i t y ( l 0 l ) . T h i s f i n d i n - sc o n t r a s t e w d ith the studyof K i k u c h i a n d S h i r n m e i( 1 0 2 ) w h o r e p o r t e dt h a t culturin-eyoun-rrabbitarticularchondrocytes with HA of 0.3 X 106Da clecreasecl proteoglycansvnthesis'nvhilepreparations with MWs > 0.8 X 106 Da stirnulatecl it. Moreover'.the releaseo1'pnlteoglycansfnrrn the nratlixin the presence or absence o f I L - l B a l s r )u ' a sc l i n t i n i s h ebcvl c o c u l t u r i n -wui t h the high MW prepalationsbut not with the low MW species.In a str-rd1' on proteoglycansynthesis in bclr.'ine articLrlarcartilageexplantsin the presenceand absenceof IL- 1B.it wasreportedthat HA penetrirtecl the cartilageand iiccumulatedin the pericellularmatrix of chondrocytes therebyrnaint a i n i n gs y n t h e s i sw. h i c h w a s s u p p r e s s ebdy f L - l B in the absenceof HA (103). Evidenceto support this finding was providedby a study that showed that a HA fiaction with an MW of 0.8 x l0ô Da enhanceclprolifèrationand matrix synthesisby I N T R A . A R T I C U L AH RY A L U R O N A NT H E R A P YI N O S T E O A R T H R I T I S immaturerabbitchondrocytes culturedin collagen gels ( 10.1).Similar lindings were reported fbr equine chondrocytesand cartila-eeexplantscultured in the presenceof HA ( 105). The turnoverof componentsof the cxtracellLrliir matrixof cartilageis largelydeterminedby thc fine balancebetweenthe activit,vof rnatrixrnetalloproteinases(MMPs anclthe a-ggrecanilses) anclthcir' r e s p e c t i v ei n h i b i t o r s( T I M P - 1 . - 2 . - 3 . - - 1 )( 1 0 6 1 0 9 ) .E x p o s u r eo f I L - l a s t i m u l a t e b d c l v i n ec h o n x HAs rvith MWs of drocytesto 0.-5 l0('. 1.0 x x lOn and 2.0 l0' Da haclminirnaletfect on tl.rtproductionof str'omehsin(N'lN'lP-3) bLrtproclucecl a markeclconcentrationancl N,IW-dcpcnrlcnt cnh a n c e m e notf T I M P - I r e l e a s e o n c e l l sc u l t u r e df i r r ' 2 - t ld a y s( l l 0 ) ( F i - g- 1 ) I. n a s u b s e c l r . rset nu td rt I | | t . ex vivo culture evicience\\ u\ pro\ idctl thlrt I..\ t l . r e r a p yu'i t h H A ( o 1 'N 1 \ \ ' o t ' 0 . 8 r 1 0 " D l t attenuatecl nitlic oricle raclicalnreclirtc'rl cl.rontlrt,cvte apoptosisin a rahbit nroclelof OA. Recentlvit vuasreported( I l 2) thatthe anti Fasinducedapoptosisof culturedhumanchondrocytes was reclucedu'l.renthey were culturedin the prescnceof HA with ar.rMW of 0.5 x 106-0.73x 106 Da. In this stutly,the anti-apoptotic effèct of HA was signilicantlyclecreased by the adclitiono1'both a n t i - C D : 1 a4 n d a n t i - I C A M - l t o t h e c L r l t u r e sT.h c c o m b i n a t i o no f t h e 2 a n t i b o c l i chsa t l a n u r l d i t i r e inhibitolv effect. Thesc clata suggesteilthut thc a n t i - a p o p t o ta i cc t i \ i t ) ' o f H . \ r i u s n r c r l i l r t etr' lr r i t ' b i n d i n gt o s p e c i l i cc e l l u l a rr e c c p t o r sT. u o t r t h e r HAs n'ith difterent\'IWs also ucrc cxarrincclbr ( I l2). Significantly'. theseinvestigatofs HA of Nl\\' -0.06 x 10(' Da did not reduce the anti-Fasinduced apoptosisof chondrocytesuhilc H,\ ol h i g h e rM W ( 1 . 0 X 1 0 6D a ) w i r sl e s se t Ï e c t i r et h a n H A w i t h a n M W o f 0 . 5 X 1 0 . - 0 . 7 3X l 0 " D a . The known stirnulatoryaction of tlbroncctin frargments on the enhancedreleaseol' proteoglyc a n s f i o m b o v i n e c a l t i l a g ei n c u l t u r e( l 1 3 ) w a s abrogatedin the presenceof HA of MW of 0.8 x 1 0 6D a ( 1 1 ; l ) .E x p l a n t so f h u n t a na n k l e o r k n e e joint cartikigeswere used in these latter expenrnentswith HA cultureconcentration of 1.0mg/rnL maintainedover 20 days. Proteo-elycan levels rn the tissueswerepreservedby enhancement of therr synthesisalthclughaggrecrnaseactirity \\'ils not completelysuppressed. It was proposeclthat the prcltectiverole of HA undertheseconditionswas achievedby its blockadeof fibronectinentry into cartilageandthuscontactwith chondrocytes. How- 50 f 40 30 20 o E o o E 10 o ,_-,..,K_ 1250 r.'-- TIMP-1 1000 o 750 500 = F 250 0 Exposure time (days) Fig 4. Effects of HAs of different MW on the p r o d u c t i o no f s t r o m e l y s i n( M M P - 3 )a n d t i s s u e TIMP-1) i n h i b i t o ro f m a t r i x m e t a l l o p r o t e i n a s e -( 1 b o v i n ea r t i c i n c u l t u r e so f l L - l a l p h a s t i m u l a t e d ( n ( ular chondrocytes. ) Control+ lL-1a, ) HAM W = 0 . 5 x 1 0 6D a ,( r . ) H A - M W= 1 . 0 x 1 0 6D a , ( f ) H A - M W 2 . 0 x 1 0 6D a , ( m ) C o n t r o l - l l - 1 o . T h e s e s t u d i e ss h o w e d t h a t w h i l e n o n e o f t h e HA preparationsreducedstromelysinactivity in lL-1 stimulated cultures of chondrocytes and m a y h a v es l i g h t l yi n c r e a s e dM M P - 3l e v e l s ,T I M P p r o d u c t i o n w a s m a r k e d l y e n h a n c e d ,p a r t i c u larly by the HAs with the higher MWs. lt was suggested that the net result of these effects w o u l d b e a r e d u c t i o ni n c a r t i l a g ec a t a b o l i s mi n t h e p r e s e n c eo f t h e h i g h M W H A s . * P < . 0 5 , * * P < . 0 1 ,* x * P < . 0 0 1 M . o d i f i e df r o m Y a s u ie t a l ( 11 0 ) . ever. the stimulatoryeffèctsof HA on proteo-ulyto be via an inclependent can synthesisappearecl mechanism. IN VIVOEFFECTS OF HA IN ANIMALMODELS EffeÛ.so.fHA irr Artttlgesic urtd Artti-itt.fluntntutort AttitrtulMrrlcl.s The HA rnodulates acuteand chronicinflammamodelsand tion in a doselelatedmannerin anin.ral to be relatedto its this ef-fecthasbeenhypothesized rrodulation of the early stagesof the immune p r o c e s s( l l 5 , l 1 6 ) . l n t h e s t u d yb y I a i e n t ia n d D i Rosa (l l5), adjuvantarthritisin the rat was suppressecl by usingHA of MW of 0.5 x 106-0.73^ 20 l 0 ( ' D a w h e n i t w a s - e i v e ns u b c u t a n e o u s l rB, .e c a u s e thc ntt AA rnodel is cl'iven bv T-lvnrphocyte acti vatit'rr.r.tl'rc investigators sLlggesteclthat HA nas r n o d u l a t i n gt h e c a r l v s t a g e so l i n r n t u n ep t ' o c c s s i n - u ( c e l l u l a r a n t i g e n p r e s e n t a t i o lat n d / o l r e c o g n i t i o n ) . T h c a n a l - u e s i ce l l ' c c t s o f H A l r a s b e e n i n r e s r i g a t e c li n I a n i m a l n r o d e l s o 1 'p a i n . t h c a c c t i c a c i c l r , v r i t h i n gt e s t m o d e l ( I l 7 ) a n d t h e b l l c l v k i n r n ( B K ) l e t r o s l a d e I A a d r n i n i s t r a t i o nn t o c l eI t I 1 7 .I l 8 t . A H A p r c p a r a t i o nu ' i t h a n M W o f 0 . 1 J 6X l 0 ( ' l ) a n ' a s e t f e c t i v e i n l e d u c i n g t h c h v p e r a l g c s i ai n d u c e c lb \ , both these nrcthods tbr up to 7l lrouls ultcrr it r,i,as l u s c d o r , e r t h e c o n c c n t r a t i o n r a n s e o 1 ' 1 . 5 -1 0 . 0 r n g / n r l -l A ( l l 7 ) . I t u a s n o t c d t h a t o t h c l p o l v s a c charicles( rrethr'Ice-lI Lrloseanclchonclr'oiti n polvs ull a t e ) u ' i t h s i n i r l a r v i s c o s i t l o r p o l v a n i o n i cc h a r a c t e r i s t i c s t o H A e x h i b i t e c ln o a n a l c e s i ca c t i \ , i t l i n t h e s c p a i n n r o d e l su ' h e n u s e d a t t h e s a r n ed o : c s . I n t h c e a r l v s t u d y ( l 1 7 . t .t h e i n v e\ t i g u t o l ' \ s r . l g g c s t e d t h a t t h e a n a l g e s i ce l ï e c t o l ' H . \ u a s r n c t l i a t e d b y i t s a b i l i t v t o b i n c l p a i l t p r . o d uier ) r p e[ r r i t i c s o r p r e V e n tt h c i r i n t e | a c t i 0 n $ i t l t t h c i I P l r i t rr . ' . t ' l r t o r s . H o u c Y e r ' .t h i s e r l t i i - l n a t i o n\ \ i t \ l i i t ù l | c r i : c t l ( | l 8 ) * ' h c n t h c a n a l g e s iùct 1 e c to\ 1 ' H . \ :u i t h \ l \ \ . o l ' 0 . 0 - 1x l 0 ( ' . 0 . 3 1 x 1 0 " . 0 . i { ( r ^ . 1 0 " . l n t l l . . l r l 0 " D a \ \ ' e r ec o n t p a r e ctl t r c r a l u a t r n - ltrl t c r i a l k i t r g behavior of rats aclntinistefeclIA IlK. This stucll shou'edtlrat HAs u,ith MWs o1'0.u6 x l0'' and 2.3 x l0t' Da had alnrost iclentical potcncr ancl duration o1' ac1ic'rnin tlris rnodel. n hclr.us H.\ t t l i - u o s a c c h a r i c lc o s n t a i n i n g 6 - f i n r o n o s u s l r lr r r r i l : a n t a g o n i z e dt h e a n a l g e s i ap r o c l L r c c lrrl r t h e h i , ' l r c t ' M W H A s . N I o r c - o v e rt' h. c a n u l s c s i er . l ' l c e to 1 H . . \ \ \ ' a sn o t p r e v e n t e ( b l t p r i o r u ( l n l l ) i \ t l i - r t i ( )on1 u l l K a n t a - u o r t i s1to t h c a n i r , t r l s i n r - l ruet r n c t h a l H . \ u u s n o t s i n r p l v b l o c k i n g t h e B K r c c e p t o r .T h c s c l i n c l i n g s s u g - u e s t etdh a t H A w a s s o r l r c h o n i n l l L r e ncinS p a i n t l a n s r r i s s i o ni n t h i s a n i n t a l n t o d e l b r i n t c t a c t ing nith CD.i.l receptors irncl possiblt otltel' parn GHOSH A N DG U I D O L I N [:/|ccts rll HA in Artitrtul Mtilel.s o/'OA l n t h e a n t e r i o r c n r c i a t e l i . u a r n e n tt r a n s ec t r t r n ( A C L T ) O A n r o d e l i n t h c c l o - u(.r r v e e k l r l A i n j c c lions of HA of M\\' 0.5 X 10"-0.73 r l0'- Da. u'hcn gircn cithcr I vn'eeo k r l 0 u ' e e k sa l ' t e li n c l u c i n g t h c c x p e l i n r e n t a lO A . u e r e f e p o r t e dt o l e d u c c o s t e o p h Y t e \a n c lo t h e r p a t h o l o g i cc h a n g e si n c a | t i l a s c . s l n o r i a l r n c n r b r a n ea . n c l n r e n i s c i( l l 0 . I l I ) . RcrlLrcccl oteoglvciln cie-uraclat ion anclertractibi | l)f i t r t o s e t h e r u i t h i n r p l o v e c lb i o c h e r l i c r L al n r l h i s t o nrorphonretric scores o1 caflilage clanragc also \ \ ' e r e n o t e d i n t h e H A - t r e a t e d a n i n r a l s .A d c l i t i o n alll'. it \\'as su.g-gested 1l'onr the rrorphologic data t h a t . a t i e r I A H A t r e a t n r e n t .c c l l s o 1 'c l e s t a h i l i z e d j o i n t s u ' e r e r r ( ) r e \ i a b l e a n c l n r c t u b o l i c u l l t a c t i re a n d t h a t t h i s e f 1 è c tu ' a s n r a i n t a i n c r l i l ' n t o t ' ct h l L nJ l r l o n t h sp o s t t | c u t n r e n(t l 2 l r . \ \ ' c n z c t a l t l l l t a l s o u s c ' ttlh e . \ C ' [ - l ' c a n i n eO A t t t o r l c l l r t t t : t L r t l i c t lt l t c c h a n s e : i n r l L r c c di n p a t e l l a ! i t l ' t i ] i l g ù \. 1 .( r . t t r t t l l l I l l g l t t l l : l l l t c t s u r ' - 9 C r A t.tlt1 1 1 ; 1\ 1\ c: | c u t l n r i r r i : t c rt l- e5 \ ec k l r I A p l a c e b ( )o r o 5 Il \ r\l\\ 10"0.'.1 10"Da) injcctions. e( ) n ) n r ù nl!l r - ! l ( ) r r c c k : i r t t i r | t s a c r i t i c e . H i s t o p l t h o l o u i e i L n r lc l ù a t f ( ) l lt r . l n . l n l s r i o l t t t t i e t ' o s e t t p r , \ t u d i c \ : h o s e t l t h u t - i u c c k l r i i t . j r . c t i o nosf t h i s s i z u H A d e l u re r l t h c l ) 1 1 ) ! l t ' c \ \ r ( ) o r 'ft d e g e n e r a l i cr c h a r r . e eisn t h e p a t e l l a l c a r t i l a s c . I n a n o t l r e rs. t u d r , u s i n - ut h e a r l u l t c a n i n e A C [ - T n r o d e l .S n r i t hc t a l ( 1 2 3 . 1 2 - 1i n) i e c t e dt h e u n s r a b l c j o i n t n ' i t l t c i t h e r s a l i n eo r H A r , i t h a n M W o 1 '1. 5 u 1 0 " 1 ; , , I d u r a l t e r \ L l r g e r va n d a t u ' e e k l t ' i n t c - r r u l : t h c l c l r l t c r - l o l r t o t u l t r l - r r n . i e c t i o n sT.h e a n i t l a l s -['he n el e k i l l c t l I I r r c c k ' a l i er , \ C l - t r a n s c c t i o n . r L ' \ u l l \ o l t h c s c c r p r ' r ' i r r r e r r t rl c - t l S n t i t h e t a l t Ili.Illt t o c o n c l u t l ct h l i t u r l r n i n i s t l u t i oor rl t h i s s i z c H . \ p l c p a r . u t i r r ni r r t o t l t t O , \ . j o i n t s h a c l n o c t l e c t o n t l . t c r o l u r r r c . e o n c e n t t ' a t i o no. r M W o 1 ' e n r l o s c n o u s H A p t ' c s e n ti n S F . F o c a l u l c e r a t r t r n a n d u t l . j u c c nht r p c r l r r r p h l o 1 ' a r t i c u l acl a r t i l a g eu ' i t h producin-upathu'a),sthat are presently unknou n. T h r o u g h a n e l e c t l o p h r s i o l o g i ct c c h n r q u eo f l s - o s t e o p h r ' t o s i sr t t h e . i o i n t t . r . l i r ' - u i \n\sc t ' e er ) n t n t o l t p a t h o l o s i c o b s c r r a t i o n s i n t h e A C I - T ' . j o i n t s .A l - s e s s i n -er rx p e f i m en t a l p a i n i n a n i n t r l s . S h i m a z a k ic t a l ( l l 9 t s h o u . ' e ct h l a t I 0 . t 1 6 X 1 0 " D a l l ' a c r i o no 1 ' t h o L r g ht h e -e x t e n l o f ' o s l e o p h y t o s i sa n d s v n o v i t i s \\'ùrc not leduced bv thc HA treatltlellt. cartilagr. HA afkrrded an anal-lesic etÈct. Although no receptor studies lvele undertaken bv these inr.estiqa- hvpertlophv as incliciitedbv prote-oglrcanler,'clsirr t h c t i s s u e s u a s d e c r e a s e d .O n t h e b a s i s < t f t h e i r ' l i n d i n g s . S m i t h e t a l ( 1 2 3 . 1 2 . 1s) u - u g e s t etchl a t t h e tors. thev suggestedthat HA inhibited thc interaction betu'een BK and its receptor locatccl at the nerve endin-ssand concluciedthat HA possiblv acts as a rnoclulatorof thc neurophl,siolngic condition o 1 't h c j o i n t . analgesic cllèct contèl'r'eclb1, HA administration a l l o u ' e d a n i r n a l st o b c a r r n o r e u ' e i g h t o n t h e u n s t a ble.joint. M a r s h a l l e t a l ( 1 2 5 ) u s c c 'al r t h r o s c o p vt o t r a n s e c t INTRA-ARTICULA HR YALURONAN T H E R A P YI N O S T E O A R T H R I T I S 1.0 the ACL bilaterally ancl unclertakepartial neLlrectomv in adult nron-rreldo-gs.Anirnals were aclntrni s t e r e d3 w ' e e k l v I A H v l a n G - F 2 0 ( a m i x t u l e o f chernicalll' cross-linketl HA and HA isolateclfrorn cock's cornbs) with MWs in the orclcr of 6 .. l 0 ' - 2 3 . 0 X l 0 o D a o r s a l i n c i n . j e c t i o n sf w e e k s o r I months afier surgerv. All -rroups were killecl 6 rnonths latel and joint tissuc clarlase u,us assessecl b . , ' u s i n g a s t a n d a r dl n e t h o d o t h i s t o l o g i c s c o l i n g . T h e a n i m a l s t h a t r e c e i v c dt h e l a t c t l e a t n t e n tL - l r l a n protocol hacl si-enificanllv less se',cre f)A cont parecl with the plucebo or earlv HA treutrlent groLrps. An importlLnt stu(lv on the ct'tects ot rlil'fcrcnt M W - H A s o r 1 s v n o \ i t l c h a n - s e sr n t h c , \ ( ' l - r l e t i 'fhc c i e n t c l o g w a s u n c l e r t a k c nb v A s u r i c t l l l l l ( r r 5 w e c k l v I A i n . j e c t i o no s f H A r . ' , i t h\ ' 1 \ \ s o t l ) . N + ^ 1 0 " D a o r 1 . 3 x 1 0 " D u r r e r e u c l r l i n i s t c l c t iI n t o n t l t a t i e r s t t r g e r - r 'c. x c c l t t d u l i n g t h e l u s t r r e c k n h c n s i z e e c l u i ra l e n t l l u o r e s ec ' i n - l u h e lrel H . \ p r c p r i r l t i o n s t e l c u s c r l t o t l et r - r r l i n e t h c c \ t e n t ( ) l l ) ù n c 'fhc t r a t i o n ( ) f t h e c l i f t è r c n tH . . \ s i n r o t h e s r r t o ri u n t . S F s v u ' e r ea n u l rz e c l f i r l r o l u n t c l L n c P l (iE- colttent r . r h i l et h e s v n o r i a * e r e c r a n t i n e d f b r c c l l p r o l i t e r ' r u t r o nr. a c u o l a r r l e g e n e r a t i o nH. A c l i s t r i b u t i o ni.L n c l l r e a t s h o c k p l o t e i n ( H s p 7 2 ) e r p l e s s i o n .C l e a t 'd i l lercnces \\,ere noted betrveen the eftects of the l H A p r e p a r a t i o n su s e c l T . h e s m a l l e r0 . 8 + x 1 0 " D l H A p r e p a r a t i o l t\ \ i r s l l t o r e p o t c r ) t i r t l c r l u c i n q r r r f l a r n m i i t o r yc h a n g e si n t h c . r n o r r L r r n p. l r t i e u l i r l l \ l v i t h l e g a r c l t o r l a i n t u i n i n s t h ù l i h u n ( i l r r e el r l r t l r n t e n s i t l "o i H s 1 t 7 l . r r h i c h r s l r p r ( ) t c i r )r ) t ; r r k c r, ' l c e l l r i a b i l i n . S i g n i l i c a r r t l \ ,t .h e \ t f o n s c r l n r i i i r ' t h r i t i c a c t i v i t y n o t e c lt b r t h e l o w e r N I W - H A r c . l a tive to the hi-ch N'lW analo-9uecorrelateclu ith the e x t e n t o f i t s p e n e t r a t i o ni n t o t h e s y n o r , i u n t . 'fhe e n h a n c e cp l e n e t r a t i o no f t h e s n t a l l e r : i z c t l HA through the syncx,ialtissues.observedbr ,\s;.rli c t a l ( 1 2 6 ) . w a s c o n s i s t e n tr v i t h t h e s t u c l i e su h i c h e n r a n a t e df i o r r t h e L e v i c k - s r o u p ( 8 . 1 0 .I 2 7 . I l S ) which showed that trans-synor,'ialflor', und llou buffèring by svnovial HA in rabbit .joinrs * as d e p e n d e n to n i t s c h a i n l e n g t h ( F i g . 5 1 .f h e n r o r e r n e n t o f H A a c r c s st h e s v n o r , ' i ailn t i n t a o f t h e . j o i n t rvould appear. in rabbits at leâst. to be lintitcd bv the presencein this tissue of a graclicntof sulf'atccl G A G s a n c lc o l l a g e n s( 1 2 9 ,I 3 0 ) . T h e s em a t r i x c o m ponents r.vouldbe expected to restrict the clitïusion o f n r a c r o m o l e c u l e ss.u c h a s H A t h r o u g h t h e t i s s u e . a s a f u n c t i o n o f t h e i r c h a l g e a n d s i z e .a l t h o L r g ht h i s may be an oversirnplitjcation of a cornplex rela- 21 Iil 0.8 .9 () (! at) '-o o o (J 0.2 0.1 o5 '-l 90 ) 80"/" ll:li:iilalir:i l r,,:.1 l.::l:,]:.1' l..rl:litl:t,:rl K l..l,,,l:l...1 ti 530 2O"/o 2200 H A m o l e c u l a rw e i g h t( k D a ) F i g 5 . R e l a t i o n s h i pb e t w e e nH A m o l e c u l a rs i z e and trans-synovialflow as describedby Coleman etal (127l..Note that the crossingfraction for HA with averageMWs of 530 kDa was approximatefy 75%, whereas with HA of MW 2200 kDa i t w a s a p p r o x i m a t e l y2 0 % . T h eg r e a t e rp e n e t r a t i o n o f t h e l o w e r M W - H A s p e c i e st h r o u g h s y n o v i a l t i s s u e c o u l d e x p l a i nt h e h i g h e r a c t i v i t y o f t h e s e p r e p a r a t i o n si n a n i m a l m o d e l s o f O A . t i o n s h i p .N e r e r t h e l c s s c. l c p l e t i o no f C . A G s a n c lH A frorn the svnovilrm by digestion riith hvaluronid a s e i n c r e a s e ctl h e h y ' d r a L r l i cp c l n r r ' l i b i l i n o t ' t h c t i s s u e st l 3 | t . s u p p o r t i n . u t h e i i u s s r g n c rrl o l e a s p a r t -fhc r r t l r l i f f L r s i o nh u r l i c r ' . Scott et ltl t l.l I ) studr r ' r r r r l tbl e o l r c l c r l r n ee i n . j o i n l u t - t l t r - o p u t h r se us c. h a s ( ) . \ . u h c r - ci n e t c l r s c t ln t t i t r r e a t a b o l i s n tc o u p l e c l u i t h t i r n t i n i : h c t l H . - \ r l r r i c er r l u r s i z e r v o u l c l- g r e a t l ) c n h l i n e er t s e \ r t l r o n t t l t e . j o r n tc a v i t v w h i l e c o n ù ( ) n ) l t a n t l \i n el c L r s i n st h e e n t r y o f l a r g e M W p r o tcrn: ll'onr llla\ilra. The structural inter'-relation: h i p s b e t u e e n t h c s c j o i n t c o r n p a r t n t c n t s .t h e i r r c s p e c t l V em a t n x c o m p o n e n t s a n d t h e r o u t e s o f e x c h a n g c o f H A a n d o t h c f s o l u t e n t o l c c L r l c sb e t w e e n t h e n r i s s h o w n c l i a g r a n t n t a t i c a i li yn, F i g L r r e6 . R a h b i t r n o c l e l so f O A h a v e b e e n i n r l L r c c cblv I A i n . i e c t i o no f e n z v n r e s ( l . l l t . o r f i b r o n e c t i n f r a - u r n e n t s ( 1 3 3 ) . p a r t i a l n r e n i s c e c t o n i )(' 1 3 - 11. 3 5 ) . o r A C L t l a n s e c t i o n( I - 1 6 -1 3 9 ) .A l l t h e s en t o d e l sh a v e b e e n u s e dt o e v l l u a t e t h e a b i l i t y o f H A t < ti n l l u e n c e ioint tissr-repatholo.lies aticr arthropathic induct i o n . M o s t o f t h e s e s t u c l i e sh a v c b e e n c o n c l u c t e d rvith HA of MW =0.1J.1x l0" Da. Fur the most part. these rabbit str-rdieshave supported a beneficial ettect of this MW-HA with respect trl rapidly pro-uressin,rdisease ancl have proviclecleviclencethat one of the mechanislns of G H O S HA N D G U I D O L I N F i g 6 . D i a g r a m m a t i cr e p r e s e n t a t i o no f t h e s y n o v i a lc o m p a r t m e n t ss h o w i n g t h e m a j o r m a t r i x c o m p o n e n t si n t h e i n t i m a a n d s u b i n t i m aw h i c h c o u l d i n f l u e n c ep a s s a g eo f H A m o l e c u l e sf r o m t h e s y n o v i a l c a v i t y i n t o t h e c i r c u l a t i o nv i a t h e l y m p h a t i c s .N u t r i e n t a n d m e t a b o l i t ee x c h a n g eb e t w e e n c a r t i l a g e a n d t h e s y n o v i u mi s f a c i l i t a t e db y H A . b u t l a r g eM W p l a s m ap r o t e i n sa r e n o r m a l l ye x c l u d e df r o m S F . T h e e x t r a c e l l u l asr p a c es u r r o u n d i n gt h e s y n o v i a l i n i n g c e l l si s r i c h i n H A a n d p r o t e o g l y c a n sT. h e t y p e B s y n o v i a lf i b r o b l a s t sa r e t h e m a j o r s o u r c eo f H A w h i l e t h e t y p e A c e l l sa r e s p e c i a l i z e d macrophages. See references18,10,127-130) for further details. actionof HA in protectin-u cartilageis via the clown regulation of pro-inflantntatorycytokines and M M P a c t i ri,t i e si n t h e s v n o v i atli s s u e (sl l 9 ) . I n t h e s t u c l i eos f K i k u c h i e t a l ( 1 3 : 1 )I. I A H A p r e p a r i i tionswitl.rMWs of 0.8 x 10" Da anclI .c.)x l0(' Da \\"erecompal'eclin erpartial rneniscectontrntoclel w h e na d r l i n i s t e r eactl c o n c e n t r a t i o o n fs I . i o r l e: s . A n i r n a l sw e r e s i v e n 2 H A o r s a l i n el A i nj e c t i o n s pet'week imntediatell'after surgeryuntil sact'iliec 2 or zl weekslater.This short-termhistopatholouic s t u d y 'i n d i c i i t e dt h a t t h e h i - s h e rM W - H A a t l 1 r concentlationwas more el'fèctivein minirnizing early cartilagede-gradation than the lower MW preparatlon. In a seriesof pLrblications fiorn the Antiel -troup ( 1 3 7 - 1 3 9 )u s i n g a r a b b i t O A m o d e l i n d u c e db y unilateralACL transection.it was shou'nthat IA adnrinistrationof HA u'ith an avera-seMW of 0.8.1 X 106 Da affbrdecllon-q-tel'ntprotective et-fects to .jointcartilage.possiblyby thc down re-ru l a t i o no f M M P - 3 a n d l l - l B a c t i v i t yi n s y n o v i u m but not cartilage.A more recentstudy fiom thrs group also reportedthat lA administered HA suppressednitric oxide radical productionin syno- v i u n r a n c lt h e m e n i s c o i f . j o i n t si n t h c i r r a b b i tO A rnodel:however.the influenceof HA molecular s i z e o n t h e s et i s s u ec h a n g e s\ \ r l \ n o t i n v e s t i g e t e d ( l.+0). Hou'er,er'. in an earliershort-termstLrdy( 1.1I ). .1 diftelent HA preparationswcrc exantineclin the . \ C l - T r u b b i tO A n r o t l c rl i h c r et h e l ' u e r e . l i . , e nl b r . 5r i e c k s .c o n t n r e n c i r .I rnot o n t ha l i c r O A i n c l u c t i o n . . \ t s a c l i l i c r -I u c c k l f t c r t h c ' l a s t H A i n j e c t i o n . h i s t o n r o r p h o r n e t rai cn c l b i o c h e n t i c aal s s e s s m e n t u u s n r a d eo f . j o i n t c u r t i l a g ca n c l s v n o v i u m rA. l thou.ehall HA prelrarations affbrclecl someprotection to cartilage.the'N,lWlbnnulationsn'ith MW > 0.8 X 106Da were nroreaffectivethan the lower MW preparations. Openiinclalthroscopicmeniscectttmies arecommon orthopedicprocedures that are f}equentlyaccompaniedby prernaturecartilage degeneration and the onsetof OA irrespectiveof the amountof rneniscnsexcised(142-116).Tissuedegeneration and the onsetof OA is thou-shtto arisefiom the hi-chfbcal and shearingstresses imposedon artlcular cartilage and subchondralbone causedby excisionof the weight-bearing rleniscus(1.17-150). INTRA-ARTICULA HR YALURONAN T H E R A P YI N O S T E O A R T H R I T I S L.rthis respect.the OA resultin-u fnrm rneniscectorr.ry lected by aspirationfionr joints of both -sroups is seconclary. befbreeachinjectionand fiom all ainirnals 5 weeks j u s l Meniscectorny in adultsheepincluccs patholo-uic i r l - l el Ih e l l r s li r r j c e t i o n p I i r r r ' t (p) ( ) s t n r ( ) r ' t e n ) . changesin their stiflejoints. which parallelthose The MW of the HA in the SFs collectedwas d e s c r i b efdb r h u m i i nO A j o i n t s( 1 . 5l - l - 5 9 )B . ccause chromato-uraphy cletermineclby -gel-permeation o f t h c s es i m i l a r i t i eas n d t h e r e p r o d u c i b i l i tol 'f t h i s coupled u'ith rnulti-angle Iaser-light scatterins procedurein this anirnalrroclclit has beenextenphotomctrl,.Thc -uel-pcrmeaticln chromatography sively usedto investi-gate currentanclnovel antistepallou,ecl sepalationof the SF proteinsfl-omthe a r t h r i t i ct h e r a p i e s( 1 5 6 1 . . 5 7I 6 . 0 -1 6 2t . T h e o l r n c H A . f a c i l i t a t i n st h e u s e o f m u l t i - a n g l el a s e r - l i g h t moclelof OA also has bccn useclto evaluatethe scattelin-rfil' thc tlctcrntinationof its MW. The ef'fectsof IA HA pfepafations of ciif'felent MW on lcsults ol' this stuch showcdthat both HA prepagait. serum biochenricalmarkers.cartilâge.bone. l u t i o n si n c r e a s ctdh c N , l Wo 1 ' e n d o - e e n o HuAs i n S F ( I 6 3 -I 6 7) . i i n d s y n o li a l t i s s u en t e t a b o l i s m c o l l e c t e dl i o n r t h e O A j o i n t s b u t s a l i n ei n j e c t i o n s In a stuclt'usit.t-g the ovine OA ntoclclto inrcsrlicl not. \\'hen tlic ureanposttreatment changein t i - c i i t et h c r e l a t i v ec l i n i c r l . n t o l p h o l o e i ca. n r l h i o group H,\-\l\\ tirr euch \\'aserpressecl as a perc h c r n i c a el f ' È c t so 1 'I d i l ' l è r c n tH A p r e p u n r t i ( ) n \ . e e n t l i s c h l i r r g lcl ' o n rt h c b l s e l i n ev l l u e s .t h e -uroup a n i m a l su e r e - u i v e n. 5u c e k l r I A i n . j c c t i o nos1 ' H . \ s H . \ p l c p l l r r t i o nu i t h \ l \ \ ' o 1 0 . 8 + X l 0 ' - D a w a s \ \ i t h M W s o f 0 . 8 - 1x l 0 " D a o r ] . . 1x l 0 " D l , I l o t l r ol-rrcrr HA in r'clto irtcrùu:ethe \l\\' of cnclo-renous p r c p a r a t i o nisn r p r o v e ctlh t - c l i n i c l l s r c n s i n O . \ . j o i n tS F b 1 7 6 ' i . T h i s i n c r c a sicn M W u ' a ss t a t i s s h c c pa . s c l e t e r n r i n ebcr l f o r c r -p l a t ea n u l r : i : I l ( r . jt . ticullr cliflèrentto the nreanHA valuescletermined H o r i ' e v e ri 'n. t h i s s t L r d rt'h. c i n t p l o r e cul c i c h t - b c a r ' lbr the physiologicbufferedsalineinjectedgroup in.r on OA joints observeclin both HA-treatetl (P : 0.03) (Fi_s7). This resultcontrastedwith the -groupsuas associatedwith incleasedgross llorHA MW values obtainedfbr SF obtainedfrclnr phologicalscoresin cartilageand enhancedosteoanimalswho recei"'edthe high MW HA preparaphyte developmentat the joint rrargins. It was tion. u hclc an incrcaseclin N'lW of l6% was proposedthat the increasedweight-bearing on thc o b s e ne d { F i g 7 ) . joints afhrded by HA treatlnent meniscectomized \ l o r c r e c e n t l r t. h e o r i n e [ r i l a t e r al la t e r a n l renrsw a s r e s p o n s i b lfeb r t h e i n c r e a s e o c ls t c o p h r t cl i l ' pl r o t o c c c t ( ) n r J r l o t l c l l r n r l t h ù \ i l n r ù c r p c l i n r e n t a ()lt ll.rl.rL-11g-(l rnation.Thc h i ghcr N'l\\'-H,\ prcparati r r c o l u r u r e r l u r c c r t l r i l r [ o t h c ' c h a n g e s i n r h c olo-cit o p r o v o k e a g r e a t e rc a r t i l t s e h r p c r t r o p l t r er e priranr.-ters cll of t'rlnr in.jectccl SF u:piratu'cl .joints s p o n s ea s a s s e s s ebc1l 't h c n L r n t b eort c h o n d m c r t c - 5 r r e c k ' ; r r e r i o u s l rr i i t h H A s o t ' N 4 W - 0 . - 5x c l o n e sa n c lc h o n d r o c r t ep\ c r c l o n c ' t h a nt l ' r cI o u e r 1 0 " - 0 . 7 1X 1 0 " D a o l i . 0 X 1 0 " - 6 . 9X 1 0 " D a MW-HA prepiu'ation. Moreover.the biosvnthesrs r5S-PGs t l 6 9 t . I n . j c c t i oonf t h c k r i ' r ' cM r W HA significantll of by cartila-eeexplants clerir,eclfronr (elasticity)and visinrprovecl SF storage modulus joints of animalsinjectedwith the hi-cherMW-HA postinjection cosity significantly more than sahne was less than fbr thc corresponding cartilagesof prepalation. or the lalger MW HA animals who receivedthe lower MW analogue Thesefindin-es wereconsistentwith the studvof (r 6 4 ) . ( 1 2 6 ) A s a l i e t a l a n d s u g - u e s t et hda t I A a d r n i n r s I n a s u b s e q u e nstt u d y ( 1 6 8 ) .t h e o v i n e n t o c l e l prepiirations tration of HA of MW ll'ithin the range was usedto e."'alnate the relativeetfectsof HAs of x x of 0.5 1 0 6 - 1 . 0 1 0 6D a w e r e m o r e e f f e c t i v e differentMW on the moleculalsizeof HA remarrrt h a n t h e l i i r - s e rH A s ( M W > 2 . 3 X 1 0 6 D a ) a t ing in SF of OA joints 5 weeksafierterminationof restorin-e synovial fibroblasthonieostasis and the treatment.Animalsunderwentbilaterallateralrrreb i o s y n t h e s iosf H A . G i v e n t h a t t h i s a n a l y s i sw a s niscectomyto indr.rce OA and were then divided undertaken sonre5 weeksafterthe last IA injection randomly into 2 equal-sizegroups. One -uroup of theseagentsand that IA HA has a half-life of received lA saline into I ioint and HA (MW (20 hours. it is extremelyunlikely that the rn0 . 8 4 X 1 0 6D a l i n t o t h e e o n t r n l a t e rjaoli n t . o n c ei r weekfbr 5 weeks.contmencingl6 weekspost-OA creasein MW or rheologicalcharacteristics obinduction.The other group were administerecl servedwas due directlyto the presenceof residual the high MW-HA (MW - 2.3 x 106Da) fbllowing exo-genous HA in the joint. Moreover.the MW of the sameexperimentalprotocol.The SF was colsmaller HAs used in theseexperimentswas less 24 G H O S HA N D G U I D O L I N 3.0 t h e e a r l i e r o b s e r v a t i o n so l ' P u n z i e t a l ( l l l . l 7 ) ) uho repolteclclecreasecl PGH. levels. fluid volurne. t.5 u h i t e b l o o d c e l l c o u n t . P G E . . a n c li n c r e a s e ccl v c l i c l d e n o s r n er n o n o p h o s p h a t lee r . ' e l si n k n e c S F o f O A p a t i e n t st r e a t e d r " i t h a s i r n i l a r s i z e d ( 0 . 5 X l 0 ô 0.71 X l0ô Du) HA preparationF . u r t h e r n t o r c i. n a A'u x2 a o v = E l l - n r o n t h p l o s p c c t i v c r a n c l o r r i z e c lp l r c e b o - c o n t r o l l c - rtl r i a l . r h e l , \ H A ( t r t \ \ ' . . ( ) . - 5x l 0 b - 0 . 7 3 x 1 0 " D a ) a t l n r i n r s t c - r etdo s L r b . j e c twsi t h k n e e . j o r n t e f ï u s i o n s { e o n s i r l c l c t lu s u r l a r k c r o f a f l a r e - L r po f i t t f l a n r n r a t i o)n t r - r r o t l u e eu r sl i s n i l i c a n t r c r l u c t i o no f the SF rolunrc lLeconrpanieb r lv i n t p r o v c r l c n t i n r.o s v n r p t o n r s{ 1 7 - 3 ) . F L r r t h c cl r i t l e n c eo f t h e c a p a c i t vo f H A t N l W 0 . 5 X 1 0 " - 0 . 7 . 1x 1 0 " l ) a ) t c t c o n t r o l . j o i n t i n f l a r l nution was ;rloridctl b1' a cvtologic ancl cvtoi l u o r i m e t l i cs t r . r do v f t h e c e l l p o p u l a t i o n sp r e s e n tl n thc SF of pltients lvith OA particlpating ill a 3.0 2.5 o 2.0 = 1.5 E 1.0 a 0.5 0.0 Week16 (baseline) Week26 (post mortem) Fig 7. Effectsof 5 weekly lA injectionsof HAs o f M W 0 . 8 x 1 0 6D a ( - ) , M W 2 . 3 x 1 0 6D a ( - - - - ) o r p h y s i o l o g i c abl u f f e r e ds a l i n e( P B S )( i . ) o n t h e MW of HA in SF of OA sheep joints before treatment (week 16 post-surgery)and 5 weeks after the last treatments {week 26) as determ i n e d b y l a s e rl i g h t s c a t t e r i n gp h o t o m e t r y .T h e c l o s e d c i r c l e sc o r r e s p o n dt o i n d i v i d u a lH A - o r P B S - t r e a t ejdo i n t s ( n = 5 f o r e a c hg r o u p ) .( A ) N o s i g n i f i c a n tc h a n g e w a s o b s e r v e df o r t h e h i g h g r o u p ,w h i c h w a s e q u i v a l e n t o MW-HA-treated P B S . ( B ) F o r t h e H A o f M W 0 . 8 x 1 0 6D a , t h e m e a n c h a n g ef r o m b a s e l i n ew a s s i g n i f i c a n (t P = .03). t | r u b l e - b l i n d p l a c e b o - c o n t r o l l e ccll i n i c a l s t l l d v b v ( ' o r r r t k r e t a l ( 1 7 - l l .T h e H A - t r e a t e cpl r t i c n t \ h a d u r l r ' c r ' ù l s ei n t h c r o l u r n c o f . j o i n t e f f u s i o n a n d t h e l l L t r oo l P r ' ( ) t L ' i innst h e i r S F l e l u l i re t o t h e i f p l a s r n a 'fltc t S l i iI ) r ' r i t i o t . Ir'olcin\ thlrtshotetl the nrost n r r L r k e ttii c . l i r r t i n e l L r . l c tpi rc i r l b r L n t i n(.l - l f r a c t i o n r r l ! ( ) n r I l ù n r c n l . i r r r r n r u r o g l o l . r r l i ntsr .l r n s f è r ' r ' i n . r r I - a n t i t r rI r r n . i c r L r l o p l a s r r r irnr .r r rri r - I g l r c o p r o t c i n . F o l t h c r r t o : t p a f t . t l t c \ c p r ' ( ) t e i n \a f e r t o t p r o c l L r c eidn t h c . j o i n tea r i l r b u t n t u s tc l t t c r S F f r o n r t h c p e r i p h e r n l b l o o t l r i a e l p i l l r L r i e si n t h e n t e n t b r i l n e .H e n c c . t h c i r c o n c c n l r u t r o ni n S F l c l l c c t s t h e p e r n r e a h i l i t l r r l ' t h c ' r n o r i u l n r e n t b r a n c .w h i c h i n c r e a s c -rsl L r r i n gi r r f l l n l n r a t i o n .A n i n c r e a s ei n t h e S F / P r l t i o n l r . r \t h c r . c l i ) r cb e c o n s i d e r e cal r e l i t b l e i n r l r er r t o r( ) t t h e \ c \ c l i t v o l ' s v n o r i a l i n l l a n t r n a t i o n . ( ' o r n r t l o c t r L i t l 7 - l ) u l s o r e p o r t e d a c l c c r e a s ei n ec l i L r l l r i t r o l t h e S F ( l v h i t e b l o o c lc e l l s . n t o n o c l t e s . l r r r p h o er t e s . P \ ' l N s ) a n c la s i g n i f i c a n tl e c l u c t t o ni n lLetir utctl lr nrphocr"tesand tlonocvte-ntlcropl-ragc p h c r r o n p c s i n t h e H A t r e a t e c lg r o u p e ( ) n t p a r c ctlt l S F l l o n r t h e p l a c e b o eo n t f o l s . thanthatobtainecl tirr thc SF aspirated fiorr the OA .JOlnls. L A B O R A T O RS Y T U D I E SO N J O I N TT I S S U E S S A M P L E DF R O M O A P A T I E N T S A D M I N I S T E R EIDA H A I nj e c t i o no f H A o f M W 0 . 8 x 1 0 1I' -. 2 x l ( ) ( 'D a into symptomatic human ternporal nranclibular j o i n t sp r o d u c e da s i g n i f i c a nrte c l u c t i oonf t h e t o t a l amountof arachiclonic acid rnetabolites and c-v-tok i n e sp r e s e nitn S F ( 1 7 0 ) .T h i s f i n c l i n -cro n f i l n t c c l R h e o l o g i c a le v a l u a t i o no f S F o b t a i n c c fl n t r t r O A p a t i c n t s s u b . j e c t e ct lo u r t h r o c c l l t e s i so r 5 w e e k l y ' i n j e e t i o n so f H A o l \ 1 \ \ - 0 . . 5 ) < 1 0 6 - 0 . 7 - xl l 0 ô D a u l s o h a s b e c n t l e s c r i b e d r | 7 5) . T h e r i s c o elasticitv of SF frorn thc HA treated groLlp was incleaserlfcllrtive to their own prctreatnlentvirlues ancl to SFs clerir,edtnrrn.joints of the lirthrocentesis-treateclpatients. Thesc data $'ere interpreted to inclicate that lA adnrinistration HA of Nl\À' 0..i x 106-0.73 x l0ô Da irnprol'ecl cntlosenous H A c o n c e n t r a t i o na n d N { W : h o w e i . e r .t h e s t u d r i s I N T R AA R T I C U L A R HYALURONAN T H E R A P YI N O S T E O A R T H R I T I S $'eakenecibrt the Iack of statistical analvsis of the results. Aclditional support firr a cell-rnodulating el'ltcr o f l A H A ( M W - 0 . - 5x l 0 n - 0 . 7 3X l 0 ( ' D a ) u a s provicled b1-'ntorphologic analy'sisof cartilage biopsv specimens taken befbre ancl 6 r.nonthsaftcr' treatnrenl ol .10 patients sLrl'f!r'ingllorr.rgonalthros i s ( 1 7 6 ) .A r t h l o s c o p i c a n c lh i s t o l o - g i ca n a l rs i s u a s per'fblmed undel blindecl conclilions and inclicatccl that a si-tnificant recluction of articulal cartilasc clarna_te. sl'novial inllarnntalion. ancl a lestolatior-r ot'thc linin-u cells' rrorphologl,,occurrecl6 rnonths a f t e r t l e a t n r c n t( 1 7 6 ) . A d c l i t i o n a ls t L r c l i e(sl l 7 . 1 7 8 1 on the cartilage biopsy specintensshoried that HA t r e a t n l e n t s i - u n i l i c a n t l fi n c l e a s c d t h e n u n t h c t ' o f viable chondrocytes presenl. rech-rced chonclrocrte. c a t a b o l l c a c t i v i t i e s . a n d r e s t o r e c lt h e p e r i c c l l L r l u r ' ntatfix t() normality. M o r c r e . c c n t l y 'P. a s c l u a l iR o n c h e t t i e t a l ( 1 7 9 ) clescribecla clctailedmorphologic anal!sis of svnor ial biopsr specintens frorn ltatients palticipating in a larrclorlizeclclinical studl clesi.unecl to compale t h c .e f 1 è c t s( ) 1 ' H A ( 0 . 5 x l 0 b - 0 . 7 i x l 0 ( ' t ) l t ) û n d n r r - t h v I p l e c l n i s o l o naec e t a t ei n t h e t r c a t n t e n to l ' l r l i nran ancl sccondarr knee OA. Svnovial biopsr s p e c i n r c n sn , e r e c o l l c c t c c la t t h e t i n t e o l ' a r t h l o s - - copl bcfbrc ancl 6 months after either clf the IA treatnrentsand vu'creeraminecl by' li-tht and electr()n lDlcfoscopv. Thc histolo-sicstucliessl.rowedditlèrences in the c e l l p o p r - r l a l i o nasn d t h c i f d i s t r i b u t i o ni n t h e i n t i n t a and sLlhsvnoviunrfirr the 2 ty'pes of OA. Althroscopic c'xanrinationindicated that both trcatments r e d u c e c tl h c c \ t e n t o f s v n o v i a l i n l l a m r n a t i o n .H i s t o l o g i c a l l y ' .H A t r c a t n r c n t \ \ ' i r s n o t e d t o s i g n i t i cantlv reclr-rce thc nurr.rbctsancl crtcnt of ag-eregat i o n o f s 1 ' n o v i a ll i n i n g c e l l s u h i l c c n c o u l a g i n l r e p a f a t i v cp r o c e s s e si n t h e d e e p s u b s rn o v i L r n tT. h i s later efïèct was nlol'e eviclcnt in tissues biopsiecl from patienls with prinrarl' rather than scconclart' oA. Generally.both HA ancl corticosteriodtrcatI n e n t \ n r i t i s u t c csl \ n o V i a l h y p e r t r o p h ya n d i r r c r L - l \ ù ( lt h e n u n r b e r so t ' s v n o v i a l l i b r o b l a s t - l i k c ceIIs rvhi It' clccreas i ng nracropha-ues. lymphocvtes. r n u s t c e l l s . a n r l u t l i l ' r o c v t e sT.h e u l t r a s t r u c t u r l l stucliesrcr caled l rc'cluction in speciiilizedc1,toplasmicstrLrctufcs. sr-rch as thc Golgi cornplexnncl p i n o c y t i cv e s i c l c so n t h ep l a s n r au t e l l b r a n ei n t y p e B s y n o v i o c v t eosl ' O A b i o p s vs p e c i n t e nasn c le \ i Fig lt). Thc IA HA therapv c l e n c eo 1 ' h y p e r p l a s(i a partiall)'anreliorated (Fig this svnovialpathologl,, d,idt:, *{: Fig 8. Ultrathin sections of synovial biopsy specimens taken at arthroscopy.stained with uranyl acetate and lead citrate for transmission electron microscopy. (A) In normal subjects,the plasma membrane of type B synoviocytesis decorated almost completely by pinocytic vesicles.(B) These d i s a p p e a r e di n b i o p s y s p e c i m e n sd e r i v e df r o m O A j o i n t s . ( C ) T h e y b e c o m ee v i d e n t a g a i n 6 m o n t h s a f t e r H A t h e r a p y .S c a l e :b a r s h o w n = 1 p m . M o d i f i e df r o m P a s q u a l R i o n c h e t t ie t a l ( 1 7 9 ) . Table 1: Summary of Studies That EvaluateDifferent HyaluronanPreparationsUsing Animal Models of Osteoarthritis(Cont'd) Origin and MW of HA Used S e i k a g a k uH, A M W - 0 . 8 4 x '1 06 Da S e i k a g a k uH, A M W - 0 . 8 4 x 1 0 6D a H i k a r i ,H A M W . 2 . 0 2 x 1 0 6 Da H i k a r iH , A M W : 0 . 9 5x 1 0 6 Da S e i k a g a k uH, A l V l W- 0 . 8 4 x 'l 06 Da and HA IVIW= 1.9 x 'l 06 Da S e i k a g a k uH, A l V l W- 0 . 8 4 ) < 1OG Da Findings A m o u n t so f c a r t i l a g eP G s i n H A - t r e a t e jdo i n t s m o r e t h a n i n s a l i n e - t r e a t e d groupbut 3sS-PG s y n t h e s i sd e c r e a s e ds u g g e s t i n gt h a t c a t a b o l i s m r e d u c e db y H A . H A r e d u c e dF F m e d i a t e dc a r t i l a g ed e s t r u c t i o nb o t h t h e r a p e u t i c a l layn d prophylacticalu l ys i n g h i s t o l o g i ca n d b i o c h e m i c aal n a l y s i sT. h e p r o t e c t i v ee f f e c tw a s s u s t a i n e df o r u p t o 4 w e e k sp o s t F F i n j e c t i o n . B o t h H A s p r o t e c t e da g a i n s tc a r t i l a g el o s s a s d e t e r m i n e dh i s t o l o g i c a l l yH. A M W - 2 . 0 2 x 1 0 6D a a p p e a r e ds u p e r i o rt o H A M W - 0 . 9 5 x 1 0 6D a b u t d i f f e r e n c en o t s t a t i s t i c a l lsyi g n i f i c a n t . H i s t o p a t h o l o g i ca s s e s s m e n t o f c a r t i l a g e s u g g e s t e d h i g h e r M W - H A m o r e p r o t e c t i v e w h e n u s e d a t l g i Jc o n c e n t r a t i o n l V l o r p h o l o g i ch, i s t o m o r p h o m e t r l c a, n d b i o c h e m i c a la s s e s s m e n to f c a r t i l a g e and synovium from joints injectedwith HA indicated protectiveeffects o n D o t nt s s u e s . S e i k a g a k uH, A l v l W - 0 . 8 4 ,1 06 DA M o r p h o l o g i c ,h i s t o m o r p h o m e t r l c a, n d b i o c h e m i c a la s s e s s m e n to f c a r t i l a g e and synovium from joints injectedwith HA indicated protectiveeffects on both tissues for up to 21 weeks PO. F i d i aH , A M W - 0 . 5 x 1 0 6 - 0 . 7 3H i s t o m o r p h o m e t r i c a n d b i o c h e m i c a l a s s e s s m e n t o f c a r t i l a g e a n d s y n o v i u m x 1 0 6D a suggested higher MW-HA preparationsmore protectivethan HA lvlW S e i k a g a k uH, A M W - 0 . 8 4 x 0 . 5 - 0 . 7 3x 1 0 6 D a . H o w e v e r , s u p p r e s s i o n o f s y n o v i a l c e l l p r o l i f e r a t i o n i n joints of rabbits treated with HA MW - 0.84 x 106Da was more 1OG Da P h a r m a c i aH, A M W - 3 . 6 x 1 0 6D a . s i q n i f i c a n rl h a n w i r h H A M W 5-23 ,] 06 DA B i o m a t r i xH y l a nG 2 0 ,H A M W -6x106Da S e i k a g a k uH, A M W - 0 . 8 4 . , Effecto s f H A o n n i t rc o x i d er e l e a s e f r o m c a r t r l a gien c u l t u r ea n d a p o p t o s i s 1 0 6D a S e i k a g a k uH, A M W - 0 . 8 4 x 1 0 6D a S e i k a g a k uH, A M W - 0 . 8 4 x 1 0 6D a a n d n i t r o t y r o s i naec c u m u l a t i obny c h o n d r o c y t e H s .A h a d n o e f f e c o t n n i t r i co x i d e l e v e l si n c a r t i l a g eb u t r e d u c e dc h o n d r o c y t ea p o p t o s i s . E f f e c t so f H A d e t e r m i n e do n M M P - 3 ,l L - 1 ,T I t M P - g1 e n e e x p r e s s i o ni n c a r t i l a g ea n d s y n o v i u m H A h a d n o e f f e c to n g e n e e x p r e s s i o ni n c a r t i l a g ea n d s u p p r e s s e dm i l d b u t n o t s e v e r eI V I M P -a3n d l L - 1e x p r e s s i o n in synovium C a r t i l a g en o t s i g n i f i c a n t l p y r o t e c t e db y H A b u t m e n i s c a rl e g e n e r a t i o an n d P G c o n t e n ta s d e t e r m i n e dh i s t o l o g i c a l lw y a s e n h a n c e db y t r e a t m e n t S e i k a g a k uH, A l V l W- 0 . 8 4 x '1 06 Da E f f e c t so f H A d e t e r m i n e do n n i t r i co x i d e r e l e a s ef r o m m e n i s c ia n d s y n o v i u mi n c u l t u r ea n d n i t r o t y r o s i n a e c c u m u l a t i o ni n t h e s et i s s u e s H . A h a d n o e f f e c to n n i t r o t y r o s i n a e c c u m u l a t i o nl e v e l si n t i s s u e sb u t r e d u c e d n i t r i co x i d e l e v e l si n c u l t u r es u p e r n a t a n t s . F i d i a ,H A - M W 0 . 5 x 1 0 6 - 0 . 7 x3 E x t r a c t a b i l i toyf P G si n c r e a s e db y A C L Tb u t n o r m a l i z e db y H A t r e a t m e n t . 1 0 6D a T e n i n j e c t i o n sb e t t e rt h a n 6 . Ditro H i s t o l o g i cA C a n d o s t e o p h y t es c o r e sr e d u c e di n H A - t r e a t e jdo i n t s i f t r e a t m e n tc o m m e n c e d2 n d w e e k ,b u t n o t 7 t h w e e k p o s t - s u r g e r y B i o m a t r i xH y l a nG 2 0 ,H A - M W 6 B i l a t e r aAl C L Ti n d u c e ds y m m e t r i c akl n e eO A a s d e t e r m i n e db y g r o s s x 1 0 6D a m o r p h o l o g ya n d h i s t o l o g y H . A t r e a t m e n t si m p r o v e ds c o r eb u t l a t e t r e a t m e n tb e t t e rt h a n e a r l vt r e a t m e n t . T a b l ec o n t i n u e s . T a b l e 1 : S u m m a r y o f S t u d i e sT h a t E v a l u a t eD i f f e r e n tH y a l u r o n a nP r e p a r a t i o n sU s i n g A n i m a l Models of Osteoarthritis(Cont'd) Authors (year) (reference) Species Age or Body Weight OA Induction.Duration & Timing of Treatments S m i t h e t a l \ 2 0 0 1 1\ 1 2 a ) M o n g r e ld o g Adult (25-30 Kgt Asari et al (1998) B e a gIe 5 - 8m o n t h s o l d ( 7 - 9k g ) S m i t he t a l ( 1 9 9 8 () 1 2 3 ) M o n g r e ld o g Adult (25-30 Kg/ A C L T ,t h e n 5 w e e k l yl A H A c o m m e n c i n g i m m e d i a t e l yP O ,s a c r i f i c e d 7 weeks a f t e rl a s t i n j e c t i o n W e n ze t a l ( 1 9 9 8 () 1 2 2 ) F o xh o un d s 8 . 5 - 11 m o n t h s ( 2 6 - 3 2k g ) A C L T ,t h e n 5 w e e k l yl A H A c o m m e n c i n g 3 , 6 o r 1 2 ,w e e k sP O ,s a c r i f i c e d5 w e e k s a f t e rl a s t i n j e c t i o n 2 yearsold U n i l a t e r a lt o t a l m e d i a l m e n i s c e c t o m y .A t G h o s he t a l ( 1 9 9 3 () 1 6 7 ) A C L T ,t h e n 5 w e e k l yl A H A c o m m e n s i n g 7 weeks i m m e d i a t e l yP O ,s a c r i f i c e d a f t e rl a s t i n j e c t i o n A C L T ,t h e n H A s l A w e e k l yf o r 5 w e e k s c o m m e n c i n g4 w e e k s P O ,s a c r i f i c ea l l g r o u p sa t 9 w e e k s P O 4 months PO 2 mL of drug or saline g i v e n l A f o r 5 w e e k s t h e n s a c r i f i c ea l l g r o L l p s6 m o n t h s P O G h o s he t a l ( 1 9 9 3 () 1 6 3 ) Sheep 2 V e a r so d . t U n i l a t e r a lt o t a l n r e d a l m e l r i s c e c t o m yA 4 n r o n t l r sP O 2 m L o f H A o r s a l i n e g i v e n l A f o r 5 w e e k s t h e n s a c r i f i c ea l l g r o u p s6 G h o s he t a l ( 1 9 9 3 () 1 6 4 ) S h e ep 2 y e a r so l d U n i l a t e r a lt o t a l m e d i a l m e n i s c e c t o m y . A t 4 months PO 2 mL of HA or saline g i v e n l A f o r 5 w e e k s t h e n s a c r i f i c ea l l groups 6 months PO Armstrong et al (165) Sheep 2 yearsold U n i l a t e r a lt o t a m e d i a l m e n i s c e c t o m y . A t 4 months PO 2 mL of HA or saline g i v e n l A f o r 5 w e e k s t h e n s a c r i f i c ea l l groups 6 months PO G h o s he t a l ( 1 9 9 5 1) 1 6 6 ) 2 yearsold U n i l a t e r a lt o t a l m e d i a l m e n i s c e c t o m y .A t 4 months PO 2 mL of HA or saline g i v e n l A f o r 5 w e e k s , t h e n s a c r i fi c e a l l groups 6 months PO A d a m ( 1 9 9 9 () 1 6 8 ) 2 y e a r so l d Total bilaterallateral meniscectomy,then at 4 months PO aspirate SF and inject 2 mL of HA or saline lA for 5 weeks, then s a c r i f i c ea l l g r o u p s 6 m o n t h s P O G h o s he t a l ( 2 0 0 2 () 1 6 9 ) Female 7 years old Total bilateral lateral meniscectomy,then at 4 months PO aspirate SF and inject 2 mL of HA or saline IA for 5 weeks, then s a c r i f i c ea l l g r o u p s 6 m o n t h s P O T a b l e 1 : S u m m a r y o f S t u d i e sT h a t E v a l u a t eD i f f e r e n tH y a l u r o n a nP r e p a r a t i o n sU s i n g A n i m a l Models of Osteoarthritis(Cont'd) Origin and MW of HA Used A n i k a ,H A - M W1 . 5 x 1 0 6D a S e i k a g a k uH, A 8 4 - M W 0 . 8 4 , i 1 0 6D a ; H A 2 3 0 . M W 2 . 3 , < 1 0 6D a Findings U n i l a t e r aAl C L Ti n c r e a s e dS F v o l u m e a n d d e c r e a s e dS F - H Ac o n c e n t r a t i o n t ith lA a n d M W a s a s s e s s e db y a g a r o s eg e l e l e c t r o p h o r e s iTs r. e a t m e n w H A f a i l e dt o i m p r o v et h e s e p a r a m e t e r s . Vacuolad r egeneratioo n f s y n o v i a lc e l l si n c r e a s e de x p r e s s i o no f h e a t s h o c k p r o t e i n( H s p 7 2a) n d e l e v a t e dS F v o l u m ea n d p r o s t a g l a n d li e n v e l si n y e p r e s s e db y s a l i n et r e a t e dj o i n t s .T h i s p a t h o l o g yw a s m o r e s i g n i f i c a n t l d HA 84 treatment than HA 230. Evidenceof greater penetrationoh HA 84 into synovium. A n i k a .H A - M W1 , 5 I 1 0 bD a s n d f o c a le r o s i o n so n f e m o r a l U n i l a t e r aAl C L Ti n c r e a s e do s t e o p h y t e a r e g i o n s .H A c o n d y l e sa n d c a u s e dc a r t i l a g eh y p e r t r o p h yi n a d l a c e n T t r e a t m e n td i d n o t r e d u c ee r o s i o n so r o s t e o p h y t e sb u t c a r t i l a g e h y p e r t r o p h yw a s d e c r e a s e d . h i s t o l o g i c a lal yn d B a y e r ,H A - M W0 . 5 r . 1 0 6 - 0 . 7 3 A C L Tc a u s e dc h o n d r o n r a l a cor fap a t e l l a e asdetermined '< '106 Da . i g n i f i c a n t l lye s sp a t e l l a rA C b y t r a n s m i s s i o ne l e c t r o nn r c r o s c o p y S d a m a g ew i t h i . a .H A t r e a t m e n t sN. o i n d i c a t i o tnh a t t i m i n go f H A t r e a t m e n t sw a s c n t r c a lt o o u t c o m e . S e i k a g a k uH, A - M W 0 . 8 4 1 0 6D a ;S o d i u mP e n t o s a n P o l y s u l f a tNe a P P S( 2 5 m g ) , o r N a P P S( 2 5m g ) - H A ( 2 Gait analysisshowed improverrent in NaPPS group; osteophytesworst in N a P P S g r o u p , l e s s i n N a P P S g r o u p ; h i s t o l o g i cs c o r e s o f c a r t i l a g e l o w e r f o r N a P P S a n d H A g r o u p s b L r tn o t f o r N a P P S - H A g r o u p . HA mLl S e i k a g a k uH, A - M W 0 . 8 4 x 1 0 6D a N i p p o nR o u s s e lH, A - M W 2 . 0 x 1 0 6D a M e n i s c e c t o m i z e da n i m a l s g i v e n s a l i n e s h o w e d r e d u c e d l o a d i n g o f operated limb. Both HA treatments increasedloading of operated joints. R a d i o l o g i cs c o r e s w e r e r e d u c e d b y H A t r e a t m e n t s r e l a t i v et o s a l i n e b u t h i s l o l o g i c s c o r e s f o r t h e m e d i a l t i b i a l p l a t e a u x c a r t i l a g e sw e r e r n c r e a s e d when the higherMW HA was used. S e i k a g a k uH, A = rvlw 0.84 Collagenand PG content of cartilagefrom operated joints not affected by 1 0 6D a HA treatments conrpared with saline. PG synthesis in cartilageexplants N i p p o nR o u s s e lH, A M W 2 . 0 from the tib al plateaux of the medial compartment of operated joints of x 1 0 bD a a n i m a l s t r e a t e d w i t h t h e h i g h N 4 WH A w e r e l o w e r t h a n t h e p l a c e b o t r e a t e d g r o u p w h i l e t h e r e l e a s eo f P G s w a s h i g h e r . S e i k a g a k uH, A - IVIW0.84 .< 1 0 6D a M e n i s c e c t o m y a n d s a l i n e t r e a t m e n t i n c r e a s e ds u b c h o n d r a l b o n e o s t e o i d v o l u m e & s u r f a c e s w i t h i n c r e a s e dt e t r a c y c l i n e l a b e l l i n g o f c a n c e l l o u s bone accompanied by increasedcartilagedamage. These bone and cartilageresponseswere reduced by lA HA treatment. S e i k a g a k uH, A - I V I W0 . 8 4 . i 1 0 6D a C a r t i l a g ea g g r e g a t e h i s t o l o g i c a l d a m a g e s c o r e s f o r H A t r e a t e d a n i m a l s were lessthan for saline treated controls. KS-peptidelevels in SF i n c r e a s ep r o g r e s s i v e l ya f t e r s a l i n e t r e a t m e n t b u t S F l e v e l s f o r a n i m a l s given HA were not significantlydifferent from non-operated controls values. S e i k a g a k uH, A - - M W 0 . 8 4 x M W o f e n d o g e n o u s H A i n S F o f j o i n t s d e t e r m i n e d b y m u l t i - a n g l el a s e r 1 0 6D a light scattering photometry. Both HA preparationsincreasedSF-HA S e i k a g a k uH, A - M W 2 . 3 ) < 1 0 6 molecular size when examine 5 weeks posttreatment but the smaller Da M W H A p r o d u c e d a l a r g e r m e a n i n c r e a s ei n e n d o g e n o u s H A t h a n d i d t h e h i g h e r l V l WH A F i c l i aH , A M W 0 . 5 x 1 0 " - 0 . 7 3 R h e o l o g i c a lp r o p e r t i e s o f S F a s p i r a t e d f r o m j o i n t s o f g r o u p s b e f o r e a n d 5 x 1 0 6D a weeks after treatments was determined by a micro Fourier rheometer. P h a r m a c i a - U p j o hH n ,A M W : Both HA preparationsincreasedSF storage modulus and viscosity when x ' t0 6 D a 3 x 106-6.9 examine 5 weeks after treatment compared with saline but the smaller MW HA produced a larger mean improvement in these parametersthan t h e h i g h e r M W p r e p a r a t i o n ,H A M W . . 3 - 6 . 9 x 1 0 6 D a . 30 8). leaclingthese authorsto concluclethat. in at leastin the short-termr of 6 months.HA treatment was capableof colrectinga nuntberof structural and cellularabnormalities characteristic of the osteoarthriticsynovialrnernbrane towardil ntorenorrnal appearancc. The extent of the reparatir,ecffect was more er,identin prirralv OA thiin in seconclurv OA. It also 'uvassuggestecl that the reductionin svnovial inflamlnationmediatedby IA HA thertpv coulcl e r p l a i nt h e m a i n t e n a n coel s y r n p t o n t a tri ec l i e fs e \ ' eral monthsaftcr the cessationctftl'eatrlcnt.N.{or.eover.this long termanti-inflantntaton etlèct0l'H.\ w a sc o n s i s t e nwt i t h a n e a r l i e rc l i n i c l l r c 1 - x rsl th i c h indicatedthat repeatedlA in.jections oT H,\ rlere capableof letardin-gthe rate of prorressionol' c h o n d r o p a t hiyn O A p a t i e n t s( 1 8 0 ) . In this latterstLrch. it $ as shct$r.rtltatI t|catrtrent c ) ' c l e so f ' 3 i n . j e c t i o n o sf HA (NI\\' - 0..5 x x l 0 ' ' - 0 . 7 3 1 0 " D a ) o re l I r c n r s e l c c l i n i c a l l r etlèctive in reclLrcin-c the sr nt1'rtonts ol OÀ [rLrt a l s o s l o u , e c tl h e - l - l l o g r e s s i oor t1 ' c u r t i l t r s el o : : . a s e v a l u a t c calr t h r o s c c r l t i c uflnl r u : i r r cl r t i l i t l u t c t l a f t h r o s c o p i cs c o r i n g s \ s t e l n ( S o c i e t éI - r l i nuer r e c l ' A l t h r o s c o p iIeS F A ] ) .l ' e l i r t i \ ct o l u \ i t r c r h c n i p \ . Using the chan-resin the SFA scolc bt'lirle iutd aftertreatments. the perccnta-ge of patientsconsidered a success(changesin the SFA scureof less than:1points)was 557cin the HA groupcctntpared with 377cof the lava_ue group. Anali'sis of the changesin the SFA caltilege scoresfnrn'rbaselincto I vear showeclthat l67c of t h e p a t i e n t so n H A t r e a t r n e nitn t p r < x e di l s c o n t paled to 0% itr the colttlol -u|or,rp. Thr. sereritr 0l' chondropathr'(r'isual analoguescalc) al\() \\ i.r\ evaluated i n a l l k n e ec o m p i r r t l n c n tAs . h i s h l r s i s nifrcantdil'lèrencebetween-sroupsin taror ol'H,{ was fbund with respectto the lèntrtlalcondrles. tibiiil plateaux. and fèntorotibial contpartlltents overall. Additionally. the radiologice\antinarron of ioint spacewidth in the mediul contpartntent showeda minor joint spaceloss in the HA group (0..11 | 0.16 mm) cclmparedwith the lavaget r e a t e dg r o u p( 0 . 6 - 5+ l . l 7 r n m ) . Structuralmodificationin OA .jointsby IA inj e c t i o no f H A w i t h M W : 0 . , 5x 1 0 6 - 0 . 7 x3 1 0 6 Da was reportedin a randomized.placebocontrolled,doubleblind clinical studyrecentlyundert a k e n i n t h e U K ( 1 8 1 ) .I n t h i s s t u d y .t h o s eO A patientswith less advanceddiseaseat the tirne of entry. as determinedradiologically.when sub- G H O S HA N D G U I D O L I N j e c t e dt o 3 c o u r s e so f 3 i n j e c t i o n so l ' H A o v e r l 2 months.sholr'eda si_unificantly reduceclpro-sression of .jointspacenarro\\'ing(P : .021compaled il'itl.ra mal.checl placebo-treatedcohort. In the HA treatedgroup. the rneanloss of .jclintspacewiclth r.vas 0.22 + l.l mrn.whelclrsin the placebotreated -group.the nrean loss u'as 0.60 + I .l rnm per annunl. DISCUSSION There is a larsc bod1,of cviclcnccthat IA HA t h e r a p lp' r o ri c l c ss r r r p t o n r a t ilcc l i e f i n t h e p a t i c n t s u i t h k n e eO A . H o r i r ' r e r .i t s n r c c h a n i s norf a c t r o n in this regarcl()r it\ IrotL'ntial to rroclif-r' the unclerl v i n g p a t h o l o s ro l ' O . \ i r r es t i l l c o n t e n t i o uiss s u e s . T h c o r i s i n u lc r p l u n u t i i r n b v B a l a z sa n d D e n l i n g e r ' t J . lt u n t lo t h c r st J - 1 . - 1t 5 t h l t t h e b e n e l i c i acl l i n i c a l e l l r . e t so l L \ H . \ t h c r a p ri n C ) An a s r e l a t c ttlo t h e r c s t o l u t i o ror 1 S F p h rr i c u l / r h c o l o c i c apll o p e r t i e s 1 1i 5 g l r s u I P i c n r c n t t i )t i \o\ l tl s l i . t tfe l o L r n ct lo b e i n c ( ) n \ i \ t ù nut i t h t h r 'r ' a l t i ccll e a r a n coe1 ' t h ca c l r r i n i s t e r c t lH . \ l l o n r t l r c s r n o v i a lc a v i t t a n c lt h e l o n g tcrnr clticricr ot the tltel'ap)'. \ u r n c r o u si n r i t r o s t u d i e su n d c r t a k ew n ith HAs ol r llr rng \l\\'s .u'u,ere subsecluently undertaken anclarldctlsupportto the view that this r-rbicluitous GAG rnight be actin-t pharmacoluuicallvrather thiin jr-rstas a unicluebiornatelial.Those in vitro OA rrodels that compareclH,{s of cliftèrentMW i n d i c a t e df.b r t h e l n o \ t p a r t . t h a t H A s u i t h h i g h M W ( e g . > 1 . 0 X 1 0 " D r i t \ \ ù r c n r ( ) r eb i o l o g i c a l l l , rlctive t h l n H , \ s o l l r ' s s csri z c{ e g . 0 . -X i l 0 ( ' - I . 0X 1 0 " D a t . . \ t t h c ' u n r e t i n r e .o t h e r i n r i t l o s t u d r e s t h i r tù \ l n l n e r l t h c i n t e n l c t i o nosl ' H A s r i i t h r e c e p t o r ' : a t t h c c e l l u l a rl e v e l s h o w e ctlh a t t h e s r n a l l e r H A p o l v n r e r i cp o p u l a t i o nesl i c i t e ral s t r o n - e earn d clLriteoftcn contraryresponsethan the lar-eerHA populations. In vivo studiesusinq anintalntoclelsof OA and HA preparations of varving NIW afTordecl results that contrasted u ith tliose-senerated by the in I'itro OA models.Tl.rcscuninralstudiesand theil findin-gsare sunrnrarized in Table l. Although the stucliesidentifiedin Tiible I suggestthat HAs $ ith MWs between0.-5X l0ô-I .0 X 106Da couldbe the prefèrrecl fbrrrs fbr IA therapv. this interpretationis clouded by the nurnber of protocolvariationsanclspeciesLlsedin thesestudies. In both small and large animal models.the timing of HA treatmentsubsequent to OA initiu- I N T R A - A R T I C U L AH RY A L U R O N A NT H E R A P YI N O S T E O A R T H R I T I S tion and the interval before sacrificepost HA treatmentalso variablemarkedll'. Furthermore.resultsobtainedusin-grabbitntodels ofien conflicteclwith those generatedusinr lar_9e anirnalOA rnodels.This clifference lrav al'lsc becauseof speciesdit'terences. but the extcnt ot synovialinflarnmationand the rapicllate of caltila-r:edegenelationinduccclin the small anitnal joints bv the sLrrgicalprclcedures cornparedriith that seeuin lar'-ce animaljclintsmay be an intport a n tc o n s i d e l a t i o n . N o t w i t h s t a n d i nt h g e s es h o r tc o n t i n - utsh.c a n i r n a l rnodelsstudiestogetherrvith the lirnitcdnuntberot laboratorystudiesconducteclon tissue\tl'ont Ituman sr-rbjects haveprovidecla ratronalhasrsfor the pharmacologicactionsof HA antl ltot theseac t i o n sr n a vb e i n l l L r c n c ebcrl i t s N l \ \ ' . A n i m p o r t a n(t l e t e n r i n a n(t) 1t'l t e p h a f n t u c o l o g i c a c t i v i t v o f u n t a c r o n t o l c c u l:eu c h a s H A i s i t s a b i l i t y ' t o p c n e t r a t et h e c r t l l c e l l L r l a lr n u t r i r a n c l i r t t c r a crti i t h r e c e p t o t o ' \ n t a r g ù tc e l l sr t r u c c l - l n t L l l a t ei n t h e p e r i c lel u l l r e n ri r o r t n t e not1 ' t h c : ce c l l : . u h e r c i t c n n n r o c l L r l a tl L h -c l n ( ) \c n t c n t ( ) 1 ( ) l h c f b i o a c t i er n r o l e c u l e st o u n t l T l ' o r nt l t e r el l s . . . \ t m e n t i o n e cpll e v i o u s l r .: n t a l l \ l \ \ H . \ o l r s o n r c r s . r,vhichriould be c.rpcctecl to clif'fLrse freelt throLrglt t h e i n t e l s t i t i arln a t i x c. a n c x h i b i tc o n t r a s t i ncse l l u lar responses to analoguesof high MW. On thcsc it could be predictedthat thc ntostphar-srlouncls. m a c o l o g i c a l l ya c t i v e H A p r e p t l r a t i o l tr\i o t r l d b c thosethat were srnallenolr-s:h to guin lrcce\\t() thc p e r i c c l l u l am l a t r i x b u t s t i l l l a r s c L . n ( ) u stho c l r ei t t h c r e q u i r e dc e l l L r l u r ' r ' e \ p o nu\ ct i t : r ' e t e | t o r s ancl/orcontrol tl-rcntorcnrentof ilt)portantntcrliltors to and llrtrr the cells. W e d o n o t v e t k n o w u ' h a tt h c i c l e r lM W o f ' H A s h o u l cbl e t o f i r l l i l l t h e a b o l , er c q u i r e l l c n t \ M . oleo\,er.it is probabli'not a firecl size ran-ue. \'arving w i t h t h e a n i r n asl p e c ise. t h ee x t e n to f i n l l a t n n t a t i o n thtrtwould afÈct s1'nolialtissr-re pel'nierbilitrancl c e l l p o p u l a t i o nesn t e r i n -tsh e . j o i n tS. F I o l u n r e r. a t e o f c l e a r a n c er.h e o l o - e yr .n d \ o o n . H o u c r c r ' .a s alreadynoted.the animalntodelsand l'rurtran studi e s d e s c r i b e dt o d a t e s u p p o f tt h c v i e w l h a t H A s w ' i t hM W s w i t h i nt h er a n _ qoef 0 . 5 x l 0 ô -I . 0 x l 0 ô Da lepresenta therapeutically usel'ulcornprontise. S U M M A R YA N D C O N C L U S I O N S The HA is a uniqr-rentacromolecule that pcrlbn.nsa nrultitudeof biophysical.biocheurical. and cell re_eulatolyroles in joint synovial tissues. 31 Within the past :10 years. preparationsof high purity. pharmaceuticquality HA have become commerciallyavailablein a variety of fbrrns and MWs. Thesehave fbr.rncl widespreadapplications in orthopedicsand rheumatology.palticularlyfbr' the treatmentof OA of peripheral.joints.However. rrany cornpanics havcl'cgistered lA HA therapyas a device fathef than a clrug and this has fueled clebatcand resealchinto the rrechanismof actron o l ' t h i s a g e n t .i t s a b i l i t l t o r n o c l i f yt h c u n d e r l y i r r g .jointpatholo-lfin O,\. and r"hetherthe molecLrlar sizeof the pleparationis inrportantfbr theseactir'l tl e s . An earll' concept susgestecl for the mode of l u c t i o no f H A i u O A u a s b r r i s c o s r . r p p l e m e n t a t i t r n o 1 ' c l v s f u n c t i o nSaFl : h o n e r e r .t h e r a p i ccl l e a r a n c e o f H A f i ' o m s y n o r i i i l . j o i n t sa l t e r I A i n j c c t i r r n with the long-tclrr s\ nrptonratjcbcnefits to-gether experiencedby patients\\ i-r\ n()t eonsistentri,ith snch a proposal.Subsequent laboratoryinvestigat i o n s s h o w e dt h a t H A e r h i b i t e d a n a l g e s i c / a n t i inflarnmatorv anclir.nmunoregulatorl" activities. many r r l s h i c h u e l e r n e d i a t e tchl r o u g hs p e c i f i cc e l l r e e ù p t ( ) l \s. r r c l ut s C D : 1 . 1A.l t h o u g ht h e s ep h a l r n a c o I o S i el c t r r i t i c ' so t ' H A p l o r i c l c r u l n c r p l a n a t i o no f I r o r rt h i : u g ù l rùt ( ) L l lpr lr o c l u cser n r 1 - r t o r n ur et ilci e lr n O A . t h c i n r p o r t r i n eoc t ' \ l \ \ ' o n t l . r c s ca c t i v i t r e s r e n ] l t i l t e t tl r n lc s 0 l r c t l . I t t r i t l o \ t L l ( l i c \ t t . i t . t gc l . t o t . t i l t l )tcc\ o r c a l t i l a . u e ù \ p 1 1 1 1e1r 1r l t u l c s h u r c r u g g c : t c t l l c h o n c l r o p r o t e c t i r r r t r l r ' l i r l H . \ . \ l o t - c o r c r ' i.n t h e s ee x p e r i m e n t s H.\ prcpllltron' u itlr \l\\ s >2 X l0(' Da wcre r n o r . cc l l e c t i r e t h u n H A o l ' M W < 1 X l 0 ô D a . I n c o n t r a s t .s t l l d i e s L r s i n - as n i r n a l m o d c l s o f O A a n d ditferent MW-HAs have conflicted u,ith the in vitro findings. Paradoxically. in thcse anintal rnoclels of OA. HAs with MW >2 X l0('[)a rier-e |eported to be less protectir e- tO cartila-ge and svnorial cell rrctaholislr than HAs of less than half thrssizc. T h c n r e c h a n i s n r ( sf)ù s p o n s i b l et i r l t l i i s d i l ' f è r ' e n tial e-1'1cct ol' HAs on cartilage and synor,ial ccll metabolisnr al'e still the sub.ject of lcscarch but coulcl be lclated to the enhancedpenett'ationol'the smaller MW prcparations intct the tissr-rcs. thereby achievin-ghi-uherconccntration of the clrr-r-c in the pericellulal envilonrnent of the cell. The hi-ghcr concentration clif'ferentialachieved by the lowcr MW HA species relative to the lar-eerMW analogues could clicit a more potent pharmacologic response by the cell. However. experintental evr- G H O SAHN DG U I D O L I N 32 dence indicates that this explanation is far front adequate and consideration also musl be -given to recent studies in cell biology that have sl.rownthal si_unaltransdLlction and gene expression arisin.n lrom HA receptor bindin-calso can be MW-depcndent. Despite the inadequacieso1'our present knou'ledge of HA interactions at the cellular ancl nrolecular levels. there is -good evidence ll'ont anilnal models of OA and fl'orn str-rdies on huntan s)'tlovial biopsy specimens. that the structLlral rloclif'r'ing efTèctsexhibited by HA in OA .joinrs ale largelv r l e c l i a t e db 1 , i t s a n t i - i n f l u n m t r t ' r t ) .e r t o p l o t e u t i v e . and immunoregulator1,prope.rtics. T h e d a t a r e v i e r " , e cal l s o s L r g g c s t h a l c a f t i l a g e protectlon ma\' occur. not tlonr a direct etfect o1' H A o n c h o n d r o c v t c s . b u t s e c o n d a t ' yt o l h e d o w n f e g u l a t i o no f c y t o k i n e .l l ' e e r a d i c a l .a n d p r o t e o l y t i c a c t i i ' i t i e si n t h e S F a n d s y n o v i L r n rw. h i c h a c t o n c h o n d r o c y t e isi n d p r o m o t em a t f i x c a t a b o l i s r n . S y r n p t o r . n a tri e c l i e f i n O A p a t i e n t sc o n f c r r e d b 1 ' I A H A t h e r a p ym ' av in the short-ternr b e e x p l a i n e db 1 ,i n . r p r o v e m e ni ut j o i n t m e c h a n i c a l l ' u n c t i o n sH. o u e v e r .i t s l o n g e rI a s t i n gc l i n r c a l b e n e l i t sc a n o n l y b e r e c o n c i l e db y a c c e p t a n c e t h a t t h i s a g e n t l s c a p a b l eo f p h a r i l ) a c o l o g i c a l l l , m o d i l ' ) , i n . cs c r t a i n p a t h o l o g i cp a t h u ' a ) , si n O A t h a t g i V e r i s e t ( ) s Y r . n l l t o u rIsn. t h i s l e g a r d . t h e p a r t i a l r e s t o r a t i o no t s l ' n o v i a l c e l l m e t a b o l i s n r a n d n o r m a l i z a t i oonf H A b i o s y n t h e s (i s" r ' i s c o i n d u c t i o n " ) .w h i c h h a s b e e ns h o r in i n b o t h a n i n r a l m o d e l s a n d h u n r a n s u b . j e ' c tuss r n s H A s u i t h i n t h e M W r a n - s ce l 10 . . 5x 1 0 " - 1 . 0x 1 0 ( ' [ ) a .n t a r b c o f c o n s i d e r a b li en r l l o r t a n e r . REFERENCES l . L t u r c r l t T C . F r l s e r J R [ ] . H v a l u r o n a n .I ; A S E B . l l 9 9 l : 6 : t ] r c : c e o n t j l u r \ t r L r ! t u r i r r l l t r l L l r r r o n r r nI l i o e h c r l . l l t ) f i f : 1 5 1 li97-101. lse e.l L F r l s e l J R E . L a L r r e nTt C . L u u r e n lL i B ( i . I l r r l L r r i i n i u tI :r r n i i t u r r t- l.i s t r i b u t i o n I u. n c t i o n tsr n dt r r r n t r i c r . I. D l 1 . ' r\r1r c , 1l , l , ) - l l l . r ! l l L J r J L l .\ \ ) l l l l l L ) l l \ r i l l l i ) l).lf tl -1. BalazsEA. \\'atson l). I)rrll IIr. lio'cntirn \ II \ititt.i flrrrlrrrrrnt. a c i d i n s t n o v i r l l l L r i d .L \ l L r l t ' e L r l apr r r r r n t e l . ' r .r r l l t r r r l r r r o n r . S.r,tt.ll 'tllrl \ù!()r!liu\ iilr!ilùrliiil\ \lrui1ll1('\ ol ltrlilrrr0r')|tD h l r ) l L ) r 1 ù r l ! ( ) 1 1 \ ù ! l L l C l l ù CC\ .i l \ C ( ) (rttlllti ll)(ll):H\Ol \rlrillthlc ltl: htlP://unn. g l r i o l Lr vg l l l . - " 1. 11 ) i ' r ' i t n L ù / h \ r l i l f o n i r t t , H i \Ol/iirrc\t 15. \lrkclrrrrl F. ht nl l RH. Seott .lh. \lirlecLrllLrrtodeling rr.r rrtd tertirtlt I 9 6 7 :I 0 : 3 5 7 - 7 6 . - 1 . B o t h n e rH . \ \ ' i k O . R h e o l o r r o l h r r l u r o n . r t c .\ e l i r O l o l a r l n g o l ( S k ) c k h )I 9 f i 7 : S u p p,l { - 1 1 : 1 i50 . 5 . I l a l a us L - A . D c n l r n g c r. l l. . S o d i u r nl t \ a l L l r o n a lren c l j r r i n t t u n c t j o nE . c l u i n e\ ' c t S ei l t ) E 5 : 5 :ll7 l l J . l r o n - n ) i e r o s c r ) pa\n d N l \ 4 R d a t a : P o s s i b l cs h e e l su n d t i r b u l a r s t r u c t u r ei \n a q u e o u s o l u t i o r G t . l l ' c o c o nJj 1 9 9 - 1 l::l 6 5 7 1 . 1 6 . M o r r i s E R . R e e s D . A . W e l s h E . l . C o r t l i r r n r a t i o na n t l d v r l t m i c i r r t e r a c t i o ni n s h r a l L r l o n a tsco l L r t i o nJs .N , l o lB i o l l 9 E 0 : ll8:3lJl'.1(X) 1 7 . \ \ ' c - l s ht . l . R c e ' [ ) . \ . \ l o r r i s E R . ] \ 4 a c l d eJnK . C o n r p . - t r t i t e i n h i b i t i o nt i i t l c n e cf o r . p c i i t i c i n l c l n r o l c c u l i rnlt e l i r c t i o r r : i n h \ i L l u r ( ) r l r:1r .r l r t t r r r n. 'l \ l r r l l l i o l I 9 t 0 : I j f i : l l - i - S l . I S l ) r r r k r \ . l r n c rI : ( i . \ l L r L ' r h o L rl ls. cR c c sI ) . \ . S t r r d i eusl l t \ i i l L i l ( r l i r L ù . 1 , 1 1 ;I1. r1nqLr 1 r r1' l.c lnt lt t ! r t r . t i r ' r r ' l t t r r t i 0 n t te u \ L l r t n l i f l \ ! l . l i ! t r r , i lt r l i ( r \ i t l ù n t l \L l c l r n c r l . . t i\l(l ' - g n l ù nst i\t h i r rt h e l l c r i h l r e h a i n ' .. l \ 1 o l f l i o l l t ) - ( r : 9 9 : J l l\ ô . l ( . r .L l r l l ei k r . j r t L - . l - a p . r k [ - . I ) c S r r e c l tS . I ) c r n c ' e s t Je .l ( - l t e b r e e c lk) . H \ l t l u r ( ) l l l u ft ':r .| l . rrrt i , ' | l . \ t t L t tr L i l c . l l { , p c lt l c s . e n r l i t p p l i ei r t r o r s .( ' l r c r r R er I 9 9 l l : 9 8 : l ( 1 6 . i - l J - l . 1 0 . S e i x t . l [ : .( t r n r l i n - g .( . B r r s : . \ . C h e n \ ' . S e c o n c l a lavn d t c r t i a l \ \ t r L r c l r l r rLsr l h r i r l r r r o n r inn a c l r r c o usso l r r t i o ni .n r e s t i g a t e cbl r l o l l r r r . l l L t l o t i n g L ' l e c t r { )rnr r i c r o s c o par n c lc o m p u t c r ' s i r n u l l t i o n .B i o c l r en r . l I ! ) 9I : 1 7 - 1 : 6 9 9 - 7 0 5 . l l . S c o t t. l E .I l r u l u l o n a nN . ' l u l t u mi n P a r y u L . , u r oJ R h e u n t I n f l a n r r . n1 9 9 - il:5 : - l l J . l l . G h o i h P . H u r l l i l i l o kN . A d a n r \ ' . l - e n t i n iA . l n t c n r c r i u r r o T h r u l u r o n u n( h r a l u r o n i ca c i c l tu ' i t h p l r o s p h o l i p i r ll:s c l c l e r n t i n e d h r r e l y r e r n r e a t i ocnh r o n r a t o g t a p h \r.r . r u l l i - a n g l e aserl i g h t s c r t t c r i n u p h o t o r n e l r \ r r n d r H - N \ I R \ l ) c c t r o \ c i ) p \ .I n l . l B i o l M a c r o r n o lI 9 9 4 :l 6 : 1 3 7 - . 1 : 1 . 2 3 . P u s t l u uR l i o n c h e t tIi. Q u a g l i n oD . N { o r iC . t s a c c h e l U li . C h o s l t P . H r a l u n r n a r r - p h o s p h o l i pi n i t tl c r ' l c t i o r ) sJ. S t r u c t B i o l 1997:ll0:l-1(). l - 1 . H o l s s i u r rF . A .D e l o g e l l e r J - P . V a n l ) a n l n e J . c l eD e u r - 6 . C L r l l i s - H i l l ) . C i h o s hP . T h e r o l c o l h v a l u r o n i ca c i c li n . j o i n ts t a b i l i n l I l \ p o t l t c \ i sl i r r h i p d i s p l a s i aa n d a l l i e d r l i s o r d c r : . \ l e c l H r p o t h e s c sI t ) t 7 : 1 3 :I 7 I - 8 5 . 7 . C ) g s t o n, \ G . P r c s t o nt s N . T h c c r c l u s i o l o 1 l t n r l c i n b r h r r l u r o n i c a c i d . l \ l e u s r r l c n t c nbtr l i s h t \ ù i r n r ' r i 1 1.!l .I l i r r l ( h c n r 1 9 6 6 : l : 1 1 : 91 .7 l J . L e v i c k J R . S r n o r i r l l l u i t l h r r l n r L r l i eS: .u i \ l t r l l ( ) ( . 1 ô : . 1 : 5l-61. 9 . l \ 4 c D o n a lJcN l . L e r i c k . l R . H r u l L r l o n i trne ' t l r r t el l' u i t l e ' c a p er a t e t i o m l a b b i t k r r e ej o i n t s d i s p a u t c l t l n r n r r t s e l l c e t o n f l u i c l i t l ' .E r p P h v s i o l 1 9 9 : 1 : 7 9 l 0: . l - 6 . 1 0 . S c o t tD . C l o l e n r a n P . l .M a s o n R I \ j . L e r i c k . I R . C l o n c c r r t f a t i o n - c l e p c n d c nocfc i n t e r s t i t i alll o u b u l l e r i n gb r l r r u l u r o n u n i n s 1 ' n o v i a. lj o i n t s .\ ' l i c r o l l s c R 2 0 0 0 : 5 9 : - l - 1 - 5 - 5 - 1 . I l . B a l a z sI : A . B l i l l e l S O . I ) e n l i n g e .r l' l - . N l - h r u l u n r n a t e n r o l c c u l r r - s i zvea r i a t i o n si n c q r r i n ea n dh u r n u nu r t h r i t i cs v n o v i a l f l u i d sa n dt h c c f f e c to n g r h u e o ct irc c e l l s .O s t c o u r t hS l n r p S e n t r n A r t h r i t r sR h e u n rl 9 l l 0 : S L r p pl :l1 . 1 13 . 1 2 . S c o t tJ E . S e c o n d a r ls t n l c t L L r ci ns h v a l r r r - o n asno l u t i o r r s : C h e r r i c a la n d b i o l o g i c a li n r p l i c a t i o n sT. h c B t o k r g r o l H r u l L r r o n a n( C i b aF o u n c l a t i oSnv n r p o s i u n1r. 1t3. l 9 U 9 :l - 1 . 1 : 6 - 1C0h. i c t r ester.Ne\\ \'ork. Brisbrne.Turitnlo. Singrporc.John Wiler tnd Sons. 1 3 . H e a t l e r F . S c o n J H . A u a t e l r l o l c c u l c p a r t i c i p a t e si n slructurL'\ ol hrtlutonan. ol seconcl- acid in nornral iind rrthritie hrllirn llLrrrl..\rtltrrti. RlrcLrrl contparcd uith c.lec HR YALURONAN T H E R A P YI N O S T E O A R T H R I T I S INTRA-ARTICULA c h a i s n eC s N . V a n S n i c kJ . I n t c r l c u k i n -i6n s t n o r i u l l l u i d t n t l s e n r r no i p a t i c n t s\ \ i t h r l r e u r n a t o i ictlr t h r i t i sr n t i o t h e r i n f l a n r D . r r t o r va r t h r i t i d c sA. r t h r - i t i sR h e u r nl t ) 8 l l : l I : 7 8 - 1 - 8 . l - 5 . B r o z i k N I . 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Stlrtz Korac C. \'lcnnct P. \liillr'r \\. \ \\i t l r N l i c f o h c - t c r o g c n e i(t)\l r c L r l ep i l l t s c p | o t c i r r r i n p i r l i c ' 1 r 1 c l r n i c r i l l u c t i \ c a r l d c l i n i c a l l r r t o n e c l i r c( ) \ 1 ù ( ) r r t l r r i t(i' \l .i n Rheunutol I t)95:I-1:-l-l-l-{0. 1 8 . S c h l . i a kJ F . P l c r s l . \ l c l c l z u n B i i : c h c n l c l t l cK l l . \ , I l i l k c r - H e r r r r l nE n. D i t t c l c n tc r t o k i n c p r o t i l c .i n t h c . r n o ri a l t l u i c l o f p a t i e r r t su i t h o s t e o a r t h r i t i sr.' h c u n l r t o i di l r t h f i t i \ . r l i l s e r u n e g a t i vsep o n c l t l u r t h r o p u t h i cCsl .i n E r p R h c r r n n t o )1 9 9 6 : l.l: l-55-61. D. Dovlc DV. \'lackillop 2 9 . S p e c t o lT D . H a r t D J . N a r r c l r a r '-reacrire N . C i r l l i n r o r e. l R .c t l l . [ . o u l c v c ] i n c r c u s c isn s c r t L rC P l o t c i r u | c p r ! 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K o o r n n c c fL . f h e i n l l u e n c eo f h i g h n r o l e c u l aur c i g h t s o c l i u nhr r a l u r o r t r t (eH e a k r n ' ) o n t h e p r o d u c t i o no l n t i c n r t i o ni n h i b i t o r vf i r c t u r .C. L r r .Er .v e R e s - 130 . 1987:6:1.{3 7 6 . \ ' l c K e e C I N { .P e n n o \ , 1 8 . C o * n r a n i V t . B u r c l i c k M D . S t r i c t c rR N { . B a o C . c t a l . H v a l u r o n a n( H A ) f i u g m e n t si n d u c e c l r c r r r o k i nrec n c c r p r e s s i o ni n a l v e o l u rn r a c l o p h u t e sT. h c r o l e o f H ' \ s i z e a r i dC D . { " 1J. C l i n I n r e s t 1 9 9 6 : 9 8 : 2 - 1 0l .3l . 7 7 . S r n i t h N I N I .G h o s h P . T h e s v n t h e s i so f h r a l u r o n i ca c i c l G H O S HA N D G U I D O L I N b v h u m a ns v n o ri u l { i b l o b l a s t si s i n f l L r c n c ebdl t h e n a t u r co f t h e h t a l u r o n l L t ei n t h e c r t r a c e l l u i a re n r i r o n n r c n t .R h c u r r n t o lI n t 1 9 8 7 : 7I :I . l - l l . 7 8 . T a n r r n iR . R i l l a K . P i c n i n r i i k.il P . N { a c C l a l l uD n rK . H o g g \ ' 1 . L L r u k k o n e nN l . e t a l . H V a l u r o n a ne n t e r sk e r a t i n o c V t ebsr a n o v e l e l r d o c t\ i c r o u t c c u t u b o l i s r r . l B i o l C h c t n l ( X ) l : 1 7 ( l : 15lIt-I. 7 t ) . B | i l n r l t K D . S n r i t h ( . i r t G N . S i r t r o nL S . I n t f t [ r r t i c L r l u r i n j e c t i o no l h r t i l L r r r i n l rar rs t r c a t l l t e n t i r r k n e e o s t c o a f i l r f i t i \ . W h a t i s t h e c r i t l c n c c . . ,' \ r t h r i t i sR h e u ml ( X X ) : - 1 1 I l:9 l - 1 0 . 1 . t 0 . I : o r r c s t e - r . l \ ' .\ \ ' r l k i n s o n P C l . I r r h i b i t i o no l l e u k o c r . t e Iocorrotion L r rl r r l L l u r o n a i cc i c iJ. C e l l S c i l 9 l l l : . 1 8 :1- 15 l l . E l . P a r t s c hG . S c h $ u r z e |f . \ e u n t L r l l c -Jr. D L r n k l. { . P L . t e r l P . B r ( j l l H . e t i l l . \ l o ( h l l i i t i o no t t h c r n i g l i l t i o nl r n dc h e n r o t t r , ios l ' P \ l N c e l l sb r h r l L l u r o n i.er c i r lZ. R h c u n l r t o l 9 E 9 : , 1 1 I l J3:- S . S l . P r : k o E . l r l n c r I l . \ . S o ( l t . r \ t r ( )lr-]Pt . P u n c t tN i {.Foster S I . . - f r c l r t l u r r\r\ . 1 .I n h i h i t i o ni r t n c L r t r o l t l t li tl h . lr-:.rocrto l nr di : r - n / \n r c r c l c i t \ cl r r l t r ; L l r r r r r nt ri e i t l(.' l i n F r , 1R t h c L r r n l r tl o 9l i . i : I :-lI -1. t - 1 . T u r u o t oK . \ o c h i I I . . l r r t l l L\ 1 . S h i n r l r i l rSr. \ l r r i \ ' . K i t t l o k l S . c t a l . H i g h - n t , r l c r r r lul rcri - g hhr r l L l u r l r i ea c i t li n h i b i t c h e n r o t r x i sa n c p l h a r : o c t t o s ibsL l ll ( ) l I \ \ ( ) \ ( ) n l l l e n z t n r cr c l c a s e i t t d t t c e db v r c c c p t o rn r e c l i t t e sd t i l t L r l u t i o ni :n g u i n e l rp i g p h a g o c r t e s . N l i c r o b i o lI n t r n u n o l1 9 9 . 1 : - 1 8 :t70-.l t - 1 . T a n r o t o K . T a c l a \ 1 . S h i n t a c l aS . N o c h i H . \ f t r r - i Y . [ - . l l t c t so T h i c h - r n o l c ' c L r ri lvr er -i c h th v i t l u r o n a t cosn t h e I ' L l n c t i o n L r lL u i n c . rp i r : p o l r r n o r p h o n u c l clueru k o c v t e sS.c n t i n. \ r t h r i L r s I i h r L n n I ( ) ( ) . 1 : l:l- 1( ) . s 5 . P r i ' t i [ ) . S r o t t . l F . l ] r r r l t r l o t u L n - n t e d i rl tt fcoctie c t i \ cù f l a ! l . 1 r . l l t ' t . e L l . l . r l r L : ei r r L L . t rbl r a n / \ n t i t t i c i L l ll \t l r t l L r e c r l l t r t l r r , r r L , ( ) Hr.. L t l i i t r L r' :l .a I J | ( i ù |(1) nl t \ l r l L | | ( ) l l lttn( ) l r ' a L l ] r r t l l i t \ \ .( ù l l I j i , r i l t L ' rlt t L n r ll ( ) { . r - 1 : l l : l \\l. 'l'. S ô . I o l r s 1 1K 1 1. \ l k r u K . \ k r r r : L r k \. 1L . \ i t \ u i T . . \ n c | r H i r . r n oS . I n h i l r i l o r r- lrl . . t \ ( ) l l t r r r l r r r t r nor rnr tn c u t r o p l r ni lr e d i i i t c ccl u r t i l e i : er l c - l l i r t l l r t i r rCnt.r n n c te l ' i ' r L r cR. e : I 9 9 3 : 1 9 I: 8 I 9 0 . E 7 . P c l u s oC i F .P e r b e l l i n A i . T l j r n r L C i l : .T h c e f t è c ro l h i g h a n d l o r r r r o l e c u l a r - u c i g h tv a l u l o n i ca c i d o r r r n i t o g e n - i n c l u c e c l l t ' n r p h o c v t cp r o l i f è r ' a t i o rCr .u r r T h e r R e s 1 9 9 0 : - 1 7 : - i 3 7 - - { - 1 . 8 t . F o r r c s t c rJ V . L n c k i c J N I . E t l e c t t t t h r l l r r r o n i c r c i c l o r r n c u t r o p h iul d h e s i o nJ. C e l l S c i l 9 8 l : 5 0 : l l t l - 1 - 1 . l l 9 . P l c h n r P . l l i o s r n t h e s i so f l l ' u l u l o n l t e . . \ 1 t c n t :A c t l o n s I9 E S : l l : i ( r - 7 . ( ) 0 . l - f ù i l nS I ) . L c c ' P . E l T c ' c to: l l t o l r s r r l t l r t e!tll\ c ( ) \ l l l n i n r , - g l \ e r r i r r ( l h r l i l L r r r r l t L(nJ l r P r ( ) \ t l i L l l u l ( 1 iLrr J p r o d L r c t i o nb v i L t l l L r l c er ln r l L r i n\t\' 1 t ( )i\o e\ t c \ . . - \ n t. l \ . ' t R c sl ( X ) 0 : 6l : - 1 9 9 - - 5 0 - 5 . 9 1 . T o b c t t oK . \ ' r r s uTi . . \ n d o I ' . H r r a i s h iN l . N l o t o h l t s h Ni. S h i r r L r -\ r1i . c t l r l . l n h i h i l o l r c l l t c l s o l h r i i l L r l o n l no n l r r C l i t r i r e l t i t k r n ilcc i r l r c . i e a s e t i o n r l a b c l e dh u n r l n : r n o . , ' i a l l i b r o b l u s t s . l u p r nJ P h t L l n u r c ol 9l 9 l : 6 0 : 7 9 E , l . ( l l . T a k e s h i t lS . \ { i z u n o S . K i k L r c h T i . YunlrdaH. Nantiki O . K L r r n u c aKi . T h c i n r i t r o e l ' f i ' c to f h r a l L r l o n i ca c i c io n t L - l b protlrrction i n c L r l t u r e rdh e u m a t o i cslv n o r i l L cl e l l s . B i o n r e dR e s l 9 t ) 7 :l E :13 7 - 9 . 1 . 9 i . N o n a k eT . K i k u c h i H . I k c r l aT . O k a r r o t oY . H a n t a n i s h i C . T a n a k lS i . H v a l u r o n i rcc i ( l i n h i b i t sr h ee x p r e s s i oonl ' u - P A . P A I - I a n t l u P A R i n h u n l t n s v n o v i r l f i b r o b l a s tos t ' o s t c o u r t h r i t i s u n c lr h e u r r a t o i rul l t h l i t i s .. l R h e u n t l r o l2 ( X X ) : 1 7 : 9 9l7( X - ).1. 9 1 . C a m p b e l l I K . P i c c o l i D S . B u t i e r D N , t .S i n g l c t o nD K . H a r n i l t o nJ A . R e c o r r b i n a nht u n t a ni n t e r l e L r k i In -s t i n l u l i l tse h u r r a n l l r t i c L r l acra r - t i l t g et o u n d e r g or c s o r p t i o na l l d h u r r L t nc h 0 I - INTRA-ARTICULA HR YALURONAN T H E R A P YI N O S T E O A R T H R I T I S L l r o c v t e tso l l r o d u c eb o t h t i s s L r tel , p e a n r l u r o k i n l s e - t r p ep l l s r t t i n o r c na c t i v a t o r B . i o c h i n t B i o p h t ' sA c t a l 9 l l l l : 9 6 7 l:l J l 9 . { . t ) 5 . W e i n b e l g J B . P i p p e nA N { \ { . G r c c n b e r cC l S .E \ r f a \ a s c u l a r f i b n n l b r r n u t i o na n d d i s s o h l t i o ni n s v n o l i a l t i s s L r eo l p a t l e n t \\ \ i t h o s t c o a r t h r i t i a s n d r h e u n n t o i d i l f l h r i t i s .A r t h I r t i s R h e u n r1 9 9I : 3 - 1 : 9 9 61-0 0 - 5 . 9 6 . N o n a k a T . K i k u c h i H . S h i r n L r dW n . Ettcct oi sodiunr h r a l u l o n i c a c i c lo n t i b r i n o l r , t i cf u c t o r si n t h c s t n o r i u l f l u i d ( i n r i r o ) . P a t h o p h r s i o l o g vI 9 9 9 : 6 : -I1- 1 . 9 7 . I - i s r g n o lG i . G l a s s iF . P i a c e n t i nAi . C o c c h i n iB . R e n t i c l c i i G . B e r i l a c q L rC a . c t l l . H r r l L r r o n r ldt o e \ t . r oat l f c c i c \ t o ki n ! ' l I t ( l c h e m o k i n ee x p r e s s i o ri n r o s t c o l r t h l i t i cc l r o n d r o c r t elsn d s r n o v i o c r , t e sO . s t c o a r t h r i t i(s a r t i l a g el ( X )l : 9 : l 6 l - f i . 9 8 . A k a t s u k r\ { . Y r r r u n r o t oY . T o t r e t t oK . Y a s L r i T . \ n r I r ' 1. I n v i t r o e f t è c t so l h r a l t L r o n aonr . p t r o s t a i : l l r n d i[n: . i n L l t r e t i o]n. r i n t e r l e L r k i ln -i n r a b b i t a r t i c u l u lc h o n c l r o ct re s . . \ L c r l . . \ e t r l r r . 1993:lE:lll--5. 9 9 . F L r k u d aK . T r L k alrr n a l \ ' 1 .L l c r t r r\ 1 . O h \ 1 . \ : r r t l u S . K u r r t i n oF . e t r l . H r l l L r r o n i ac c i di n h i h i t .i n t t r l c L r k i In r n L l L r c t ' t l s u p c l o r i c liel n i ( ) ri'nr t r o r i n ec l r o n t l r o e \ l r 'I\n. l l i L n t l R l a, I99- 1 6 : ll - 17 . 'f. l ( X ) . S h i r t t a z .u\ . J i k k o A . I u r n r o t i , \ 1 . K L r i k c \ l l \ \ . Okadr \'. ct ul. [:tÈcts ol hrllurolit .r.itl on thc rclet\e ol p r o t c o - g l \ c l nf | 0 n r t h e c e l l n l l t f i \ i n | r L h h iet h t r n r l r o c r tceL r l t u r c s i n l h c p r c s c n c er r r d a b s c n c co l e r l 0 k i n e s .A r t h l i t i s R h e u n t I t ) c ) 3 : 1 6 : l - +- 5 7i. l 0 l . F L r k L r dKa. l ) a n H . T u k u u n r . t\ 1 . S l i t o h N l . T a n a k aS . H r l l r L r o n i cl c i r l i n h i h r t si n t c r l . ' L r k i n l --i t r t l L r c ect u l r ' l i l a c ec l e - l r i t dation..lpn J R h c L n r r r t oI 9l 9 5 : - i : . 1 J- r5- 1 . l 0 l . K i k u e h i T . S h i n t n t c i\ 1 . E l t e c t so f h \ ' î l u r o l n l l o r 1l t f o t e o g l r c a nn r c t l t b o l i v l o l l r b b i t î r t i c u l i l r c h o n t l r o c r t e si n c L t l t u r e .J p n J R h c L r r n . r t o 1 l9 9 - 1 : - 5 : 1 1 05 7. l0J. FukLrtlK a . i ) a n H . T a k t v u n t aN I . K L r r l l n oI : . S a i r o h\ 1 . T a r r a k aS . 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Bleu K. Dinakarparrdiln D . N r g r L s eH . T i s s u ei n h i b i l o f s o f r n c t a l l o p r o l e i n a s eEsr:o l u t i o n . s t n l c t u f ùi L n ( lf u n c t i ( ) n . B i o c h i n rB i o p h l s A c t a Z ( X X ) : 1 . 1 7 7 : 1 6 7 - 1 1 . 3 . 1 0 7 . U i r k c c l a l - H r n s eH n . l \ 4 o o r eW G I . B o d d c n\ 1 K . \ \ ' i n t l s o r L J . B i r k e c l aH i a n s e nB . D e C a r l oA . e - ta l . N l a t l i r r n c - t u l l o p r o t e i n a s c sA: r e l i e r i . C r i t R c l O r a l t s i o l \ { e d l t ) 9 - l : - l : 1 9 7 150. l 0 l J . A b b a s z l d e I . L i L r R Q . Y a n g F . R o s e n f t l t lS A . R o s s O H . L i n k J R . e t t l . C l o n i n c u n c l c h a n t c t e r i z l t i o ni r f , \ D . \ M T S l l . . u t â g s r e c a n a sfcr o r n t h e A D . \ N { T S l a n t i l r . . l B i o l Chem I999:17.1:23.1.13-50. 1 0 9 . L a r k M W . B a v n cE K . F l a n a g a nJ . H a r p c rC F . H o e r r r r e r L A . H u t c h i n s o nN I . e t a l . A g g r e c a nd e g r r c l r t i o ni n h u n l t r r curtilaqeE : v i d e n c et b r b o t h n t a t r i r n r c t a l l o p l o t e i n a sr ne r i r t g src-cûnilseacti\,itv in norntal. osteoûrthIitic.anci rheuntat0icl . j o i n t sJ. C l i n I n v c s t1 9 9 7 : 1 0 0 r 9 3 - 1 0 6 . I 1 0 . Y a s L rTi . A k a t s u k rM . l o h c t t o K . U n r c n r o t oJ . A n d o f . Y a n r a s h i t aK . e t a l . E l ' t è c t so f h y a l u r o n a no n t h e p r o d l l c t i r ) n o l s t r o m e l v s i na n d t i s s u c -i n h i b i t o r o f n t e t a l l o p r o t e i n a s e - l 35 ( T I \ l P I ) i n b o r , i n ea-r t i c u l â rc h o n c l r o c r , t eBsi.o n r e dR e s l 9 9 l : |3:3-13-8. 'lakuhashi lll. K . l ' l l s h i m o t oS . K u b o T . H i r a s a u aY . L o t z \ ' 1 . . \ m i c l D . E t t e c t o f h v a l u r o n a no n c h o n d r o c r ' t ea p o p t ( , \ i \ l u n dn i t r i c o r i c l ep r o r l u c t i o ni n e \ p e f i n r e n t a l l ti n d u c c do s t e o a r t h r i t i s J. R h c u n r a t ol 0l ( X ) : 2 7l 7 : l3 10. l l l . L i s i s n o l iG . C i r a s sFi . Z i n i N . T o n e s u z zSi . P i a c e n t i n i . A .G L r i d o l i nD . e t u l . A n t r - F A S - i n d u c eidl p o p t o s i si n c h o n d r o c \ t e \ r e c l l l c e db y h v r l L L l o n r nE . ridencclirl CD.l.l an.l CD5.1 ( l n t c r c e l l u l a rr d h e s i o r r r n o l e c u l a el ) i r r V o l V c n t c n tA. l t h r i t i : R h e L r nl t( X )| : . 1 - Il :8 ( X ) - 7 . I l . l . l l o r n a n d b e r gG A . H u i [ ] . . A s s o c i a t i oonf p r o t e o g l \ c a n t l c l r i r t l r r t i o rtri t h c a t a t r o l i cc v t o k i r r er n d s t r o r n e l r ' s i nl e l e r s c l r o n r c . r l t i l u c cc L r l t u f e culi t h l l b r o n e c t i nl n g l t c n t s . A r - c hB i o el t . ' n rB i o p h rs l 9 ( ) 6 : J - l - l : i l - 5 -l -. l I l - 1 . K l n - : .\r. F - - l c\r\ ' . K o c p p H . \ \ ' i l l i l n r : . 1 \ 1 .K u c t t n e rK h . I l o r n r n i l h eSr ( i . \ . H r l r l L r l o n l n\ u p l ) r ' ù \ \ r 'i\i b r o t r r ' en1 iI l i l M t c n l n r c t l i . t l c rrll i r n t r r ! cl t r l t L t r t l r lc l t r ' l i l i L ger r' p l r n l c L r l l n r c :b r c - n ] r r n ù i n !P f ( ) r ù r ) -e!llLr rs r n l l r c ' i ' .. l O r t l r o pR . \ l 9 ( ) 91: 7 : 8 5 86 9 . I l 5 I r r l c n t r\ . I ) t R r , . r \ 1 . f { r r r l L r r L r rl iree i tnl t o d u l l L t tcrsc L r t e i i r ( l ! l r r ( r l r l !r r l l l r n t n t . r t i r r .ù\ .L r ' n l ' . \ e t i o D : l t ) ( , ) - l : - l - l : - 1 - 1 - 7 . I l h . H i r k r r n " o n[ - . l l r r l l g r c nR . \ e n g e I ) . R e - r u l r t i o no f - r t r n t t l o etrc ' I i r r t c t i L rLnr l h r l r l L r r r r n il ct c i d i n \ i t r o l t r t l i n r i r o c t l e c t \ o n p h r l t o c \t ( ) \ i \ . l o e o l r o t i o l t .a n t l m e t a b o l i s n rJ. C l i n lnvest I980:66:19E--105. I 1 7 . G o t o h S . N l i r a z a k iK . O n a y ' a . 1S. r k a n r o t o ' l ' T . okuvrsu K . N u n r i k i C ) .E r p c r i m e n t a kl n e e p a i n n t o c l e il n r a t s a n c la n r l g e s i ce l t è c t o l s o c l i u r lh v a l u r o n a t et S P H t . N i p p o n Y a k u r i _ u a k u Z a s s h i l 9 [ i l J : 9 ] :I 7 - 1 7 . I l l l . G t x o h S . O n a r u J . A b c N { . \ ' l i l a z a k i K . l l a n r a i. \ . H o l i c K . c - t l . E t l è c t so f l h e n r u l c c u l a r ' \ \ ' c i g (hrll l t r r l u r i i n i c i l c i ( Li l l d i t s a e t i o nm e c h a n i s r ' nosi c r p e - r i r r r . . n tjlot li n t p i r i n i n r ' . t t s..\ n r r R l t eu n r D i s 1 9 9 3 : - 5 1l 7: E- l l . I 1 9 . S h i n r a z r k iS . A t s L r t aY . \ ' i t n t a ' h i l r LI . \ \ r t i t k a t r cl \ 1 . O k r r n r o tT o . \ l i r a t s u N l . c t a l . T h c r n l t i l r i t o rc) l t c c t so f h r l l L L r r r nlrLee r t(lH . \ ) o n c l c e t l o p l t r s i o l o t i erlcr ls l . o n r ctso r . \ p c f i r r c r l . r l k r c c j o i n t p a r l . - [ - r ' n nOs r l h o PR r r S o c .J l s t A n n L L t r l \ l ù c lr r r l ( l ( ) i : ô 0l l l o . \ i r r r t . r n l t l (, i' . l l L r t tli' ] .I ) c l l l L r c\ 1 . G e i G . S a n r s oJnC . ( ' L r r l r r oI l . a l i t L .l l t l t i r i r r l i i L L' lLl L , rrl r L rlnt rt i r l L r r o n ni nt e- i e c t i o ni nt t l r r '[ \ ) n r i\ L r k i t r . l r r t i l t c l t r L l - n r L r(tj lte( )i \ t ù o i l r t h r i it ni sc l o g s l.: I J i o e h c n r i cri r .l \ u l l \ .( ' l i n O r t h ( ) | 1 9 8 9 ' r J :l 1 7 8 - 1 3 5 . l l l . S c h i a r i n i t t o . \I.- i n i E . ( i L r i r l o l rDn . P e z z o lG i . BoltiP. N l a r r c l lN i l . e t u l . I n t r a i i r t i c L r lsi rol r l i u n h r \ u l L r r o n a ti n c j c - c t i o ni sn t h c P o n d - N u k ie x p e r i n t c n t anl t o c l eol f u s t e i t a r l h r i t i sn d o g s .[ [ : l \ l o r p h o l o - e i c al iln c l i n g sC. l i n O r t h o p 1 . 1 8 9 : 1 .:1l l1l 6 9 9 . l l l . W e n z \ \ ' . B r e u s c hS J .G r a l J . S r l u r r n r n nL l . L ' l t r a r t r L r c t u r a l t i n t l i n c su f l e l i n t r a a r t i c u l aarp p l i c a t i o no l h r u l u r o n u nr n a c a n i n cr ) r o d erlr f r r t h r o p a t h tJ. O r t h o pR e sl ( X X ) : l l J : 6 0 1 - l l . l l 3 . S n r i t hC i N . N l l c - r ' sS [ - . I ] n i n t h K D . N { i c k l e rE A . E f È c t o l i n t r a a r t i r r c l ahrr l l u r o n a t r i n - j c c t i o ni n e r p e r i r l e n t a lc a n i n e o s t c o i l r t h f i t i \..\ r ' t h r i t i sI l . h e u n t1 9 9 3 : - 1: t1) 7 6 - 8 5 . l l - { . S n r i t hG N . \ 4 i c k l e r E . { . \ l 1 e r s S l - . B r a n d tK D . E f l è c t o f i n t r r u r t i c u l r lh r l l u r o n u n i nj e c t i o no n s v n u v i a lt l u i c lh _ " - a l u r 0 n a r i n t h c e l r l r s l t r s e0 f c n n i n cp o s t t r a u n t â t i cO s t c o a r t h r i t i s . . l R h c u n r t t o l ( X )I : l l J :I - l l I 6 . l 2 - 5 . 5 1 x r t 5 " 1K 1 W. N,{anolopoulV o s. M a n c e l K . S t a p i e s . l . Dirrnvanuvich A . A r n e l i o l a t i o no i t l i s c a s cs e \e r i t v b v i n t r a a r t i c u l u rH r l l n t h c r a p vr n b i l a t e l a lc u n i n co s t e o a r t h r i t i s .O . lr t h o p R e sl ( X ) 0 : I 8 : - 1 I 6 l 5 . l 1 6 . A s a r i A . N { i v a u c hS i . ! l a t s u z r k aS . I t o T . K o n r i n a r r iE . 36 L l c h i r a m aK . N l o l e c u l a ru c i g h t d e p e n d e nct f l e c t sr r f h t a l u r o nate on thc arthritic \\,no\iunr. ,\rch LlistolCrtol lt)9li:ôl: r2 5 - 3 5 . l 1 7 . ( - o l e n r a nP J . S c o t t D . N , l a s o nR N { . L e v i c k . l R . R o l t o T h r ' a l u l o n a nc h a i r l e n g t h i n b L r l l c r i n - il n r t c r s t i t i a ln o \ \ i r c r o \ \ : r , n o r i u n t i n r a b b i t s .J P h 1 ' : i o l( L o n d ) l ( X X ) : 5 1 ô : - 1 1l l. 5 l l 8 . N I c D o n a l d. l N . I - Ù i c k J R . E l l ê c t 0 t i n t r a - u r r i c u l ihi rr l l u r o n t n o n p r e s \ u l e - f l o \ \r e l l l i r r n. r e r i r s\s\ n i l \ t L l l I t n t r r t l r u s t ] t c r i z e dr a b b i t s . l P h V s i o lI 9 9 5 : - l E 51: 7 9 - 9 . 1 . l 1 9 . C l o l c n r aPn. K i r ru n i i c hE . N l a s o nR N l .l - e ri ek . l R .. \ s h h u r s tD E . T h ! -p r o t ! ' o c l \ c r nasn c u l l r e o s l r r 1 1 i n o l l \ (cr]nI r i n st , t r a b b i ts v n o r i L r nH r .i s t o e h e nJr I 9 9 l t : i 0 : 5 l 9 - l - 1 . 1 . 1 0 .\ ' l r i : o n R \ 1 . I - c r i c k J R . C o l e n l L nP J .S c o t tD . B i o c h e r n i s t r r o l t h e s r n o r i r r n ta n d \ \ ' n o \ i l l f l t r i d .l n : B i o l o g vo f t h t S \ n o r i a l . l o i n t . . \ r ' c h e r C \ \ ' . C t r l e I r o l t B . B c n j a n r i n\ { a n d R a l p h s J R . e d s . A n r s t e r d a n rH : r r u o o d , { c a c l c r r i cP r r h l i s h c l s 1999:15-1-6-+. 1.3 l . S c o t tD . C o l e n n nP J . \ ' l a s o nR N , l L. e r i c k . l R .( i l r c o s a r r i n o g l l c r n d e p l e t i o ns r e a t l \ r ' a i s e tsh e h v d r a L r l ipct ' n l e l L h i l i t r o f r a b b i t . j o i nst l n o v i r l l i n i n u .E r p P h r s i o l1 9 9 7 : t l : 6 0 .ô1. l i l . I u , a t aH . N , l i l a L r c S h i. N 4 a c h i dAl . O n a r u . l .S r r k ; r n r o r o T . T h e e t l e c t o l s o c l i r L nhtv a l L r r o n a tocn t h e t r l t i e L t l rrt 'rr r l t i l r r : e t r e i l t e d\ \ ' i l h p a p l i n . T r . u n \C ' o n r h\ l c c t i l t O r r h r r pI l r ' \ r , e . U S A . J a p u n .C ' a n r r l l rB. l r n t l .C ' u n l r t l ilt9 ( )1. l l i . \ \ ' i l l i a n r s . l \ 1P.l l L z \r .r f l L r ri i . \ \ ' r l ( . K r L r r r n .Kr i r . H t t t r t l t n t l h c(ri '.:\:. l l r r l L r r o n i ti r ( i ( l\ u ] l I r ù \ \ a \l i l r r o r r c i t ilnr . , - . r l l ! ' n Il r c ( l i i i t c e ( l. r r t i l l r scel t o n t l r o l r : i 'L. I n r i r r r . O \ t ù ( ) i l r t l t l ' | t t . C a r t i l a g eI 9 9 7 : 5 : 1 . 1 5 - - 1 0 . l - l - 1 .K i k u c h i T . Y r n t a d i t H . S h i r n n t c iN l . I l t t c c t o l h i c h r l o l c c u l a r u c i g h t h t ' l l r r r o r r r n( ) n c a r t i l r r g ed c g c n c f a t i o ni n i l f a b b i t r n o d e lo f o s t e o a r - t h r - j O t i ss.t e o a l l h r i t i C s altrltge I99(r:J: 9 9 - I| 0 . 1 3 5 . K o b a l a s h i K . A n r i e l N l . H a r - n o o dF [ - . I { e a l l R \ 1 . S o n o d i \r' I . N f t r r i r aH . c t a l . T h c .l o l t s t e l l c f ' È c t so l h r r l u l o r r r n r l u r i n ud c ' r c l o p n r e n o l r ) \ 1 c ( r i i r t h r il ti irsl l o s i n c p l L r t i l inl t e n r s c e c t o n r r i n t r n t t r l r i t n t o t l c ' 1O. \ t c o l t r t h r i l i \C ' r r t i l r u c l ( X X ) : 8 : i59-65. 'f. 'f 1 3 6 . Y o s h i n rTi . K i k u eh i O L r i i nIL. \ ; t n t ; r l r r t l t i . S r r k l L k i b r r a Y . l t o h H . c t a l . E f t e c t so l h i l h - n t o l r e L r L u r - u c ,i L l, trll i L r n t h t l l u t - o n l t c o n e r p e r i n r c n l l lo \ t c ( ) r r t l l r ( J \ ii\n r l L r e r .ht rl t l t c r c \ e c l i o n o l f t r b b i ta n t e r i o |c | L r c i t r tlci g r r n c n t .( l i n O r l l t o I l ( ) ( ) 1 1 l9E:196-30-{. , I). 1 3 7 . Y o s h i o k aN , l .S h i n r i z uC . H u . u o o t l I i l - . ( ( ) u 1 1R A r r i c - lD . T h e e f t è c t so f h v a l u r o n t nc l u r - i ntgh . ' d c \ ù l ( ) p n t o t lr ) l o s t e o a r t h r i t i sO. s t e o a r t h r i t iC s r r t i l a g e 1 9 9 7 : 5 : 1I5- 6 0 . 1 3 8 . S h i n r i u uC . Y o s h i o k aN l . C l o u t t sR I ) . H u r * o o d f ' 1 , . K u b o T . H i r l s a n a Y . e t a l . L o n g t e l r n e t ' È c t so f l l \ l i l L r f ( J n i(L)nl e x p c r i r r e n t r l o s t e o a r t h r i t i si n t h e r a b b i t k n c c . O s l e o e r t h r r r r r C a n i l a g el 9 9 E : 6 : l9 . '1 l 1 9 . T a k a h i t s hK i . G o o n t e l R S . H a r u , o o dF . K L r L x r . l l r r . r s a u , aY . A r r r i e lD . T h e e f l è c t so f h \ a l u r - o n aonn l l t i i t r i \ n t c t a l l o p l o t e i n a s -cl ( M N I P - l ) . i r r r c r l c u k i nl - 3 9 9 t t p ( l L I 3 9 9 l t p r . a n d t i s s u ci n h i b i t o ro f n r e t a l l o p r o t e i n â s c(-' fl l N l P I ) g e n ec r p r e s s i o nd u r i n gt h e c l e r e l o p r r e not f o s t c o r f t h r i t i sO. s t e o a r l l t n L l \ C a r t i l a g cI 9 9 9 : 7 :I t l - 9 0 . l - 1 0 . T a k a h a s hK i . H a s h i m o t oS . K u t r oT . H i r r s a * a Y . L o r z N ' I .A n r i e l D . H r a l L r n r n a snu p p r e s s endi t r i c o r i d e p r o d u c t i o ni r r t h e l n e r ' r i s c uas n d s v n o v i u n r o l r a b b i t o s t e o a f t h r i t i sn t o d c l . J O r t h o pR c s l ( X ) l : 1 9 : - s ( X l . l . l - { 1 . S h i n r r zC u l .K L r b o ' l 'H . i r a s u u aY . C o L r t tRs D . A n r i e lI ) . GHOSH AND GUIDOLIN Ilirtonrorphonretric anil biocherlical cllect ol r ariorrshl irluron l n s o n e a r l r ' o \ t c o a r t h r i t i \ .. l R h c u r r a t o l l t ) t ) S : l - 5 : l S l l 9 . l-12. Rlnugcr C'. Klc'stil f. Gloetzer \\'. Kemrnler' (i. BeDeiletto KP. (Xlc(urlhrilis iil(ef lrlhroscopic prrtirl nrcni\ c e c l ( ) n r \ ' .. \ n r . l S p o l t s N 4 c i l 1 9 9 5 : l . l : l - + 0 - + . -flrppcr l-1.1. ENl. Hoor cI N\\'. l-irtc Icsults attcl nlcnisccc lonrr. .l Bone .loinl Surg Am l9ôt):51.\:.1 i 7-16. \. l - l J . . k r r u e n s c n [ . S o n n e - H o l n r S . l - a L r r i t l s c nI ] . R o s c n k l i n t l . o r l - l e r n r l i r l l o r i - t r p ( ) l l î c n i \ c c c t o l l t \ i l t l t t h l c t c s .. \ p f o - \ l ) c c t l \ c l ( ) r ! i t L r r l i n i L l\ t u d \ . . l B o n c . l o i n t S L r r g B r l 9 E 7 : ( r t ) B : itO.r. l 1 5 . \ l c \ i c l r o l r L s \ 1 . 1 .R o u l c r D l . N I c C i L r r rD v..\ilalhcrth T. \brlon P. I.inrlrlnrnrl \. ct ltl. Totlrl rrrcni:cectorrtrin rrtjolesc e n c c . , \ l h i r l l - r e i r r l i r l l o * - i r p . . l B o n c . L r i n tS u r g B r l ( X ) O : E l F 3 : ) 1 1 - ) 1. l-16. Kriiger-[;rrnkc \'l. Sichcrt ('H. KLrglcr \. TroLrillrcr' H H . R o s e r t t e r e rB . L l t t c r e s u l t rr r l l c rr r r l h r o s c o l t i pù i t f t i l t ll l a r l i l r l n r c n i s c e c t o n r \ 'K. n e e S L r r gS p L r r t . I r i l L r l n i l t o.lA r l h r o s c 1 9 9 9 : l : E I --+. l - 1 7 . S e c t l h o n r B B . I - o i r i l h c r r r i r r r :l i r n e t i o n o f t h c n r c - n i s c L r : . P ' r - i , ' t l r e r . r l rIrt r - / , / ) l l l : . t . l J S . S c r t l h r r n r B B . i l a r g r c r L re . I ) . 1 .T r r n s n r i s s i o n o t k r a d i n tlri knli t o i n l r r i t l r \ n ! ' e i i r lr ù l ù r ' c n i ùl ( r l l r c f o l e o l t h e n t c r r i s e i l ) . r r t l l : I \ l r i l i l n i r l i r l r ù \ u l l \ . ( l r \ i L r \ . r o n i t r r d c 0 r c l t t s i o n s .F . n rr0 s i r f a ( r \ 1 . ! l l \ ) - r )\ l J L ) I r L \ L , r r i L \ . r ' i fI K L r r r , . . L r . L[ 1 . I - h e c ( ) l ] t l t c ti t f r ' i r r n ( l l ) r ' . \ \ t L r ., 1 r ' l r h i l l r ' , r l r . L l l r ' | r, , 1 l l r t k n t e . O l t h o p S c l r n t l l 9 t 0 : 1l:Sl; t1. 1 5 0 . K L r r L r ' l r r rf.lL. l L r L . L l . . ' r . L . l Lr r \ r r k l r j i n l i H . L o a d - b e r r i n g t t t o d eo l t h c k n c i ( , r r l : l ) l r \ ' r ! i l l r j l r i t \ i ( ) ro l t h e k n t . e i r r i n l * i l h t t r u i t h o L t t l l r ' n i : r ' i . ( l L r O r i h , ' 1 .I l e l t l c s l 9 S 0 : l - 1 ( ) : l S . 9l 0 . l - i l . G h o s h P . N u n r i r t u) . S r r t l r \ . l l e l r r l I l . . . \ r ' n t : t r l n L S . J o h t t s o n K . T h e n r e t a b o l i cl c r I L , r ' e , r l i L t l j ( L r l l le i t l t i l i t r a l o abrtoltnal nrcchlnical loitdinu intlLrec,lirr nrcLlilrl ()r littùriil n r c r r i s c c c t o n r rl.n : J o i n t D e s t r L r c t i o ni n \ r t h r r t i r i u r ( l O \ t ( ' ( ) l l r t h t ' i t i s r. l n d e t l 3 e l g W . r l n d c r K r a a n P \ l l L n t lr r r r rl - c n t I ) l . l : \ 1 . ctls. l99i:.\AS 19:ll9 9J. 151. Little C. Ghosh P. Bcllcngcr C. N'lenisccelonrr ncr!.lse\ ilgsrecrn. decorir (PCj-S2) antl bisltcun lP(i Sl t ntttubolisnr in erltilirge. Tuns Orthop Res Soc..it)th \nnLurl \ l c c t i n g . S r n F l u n c i s c o .L I S A l t ) 9 3 : 1 8 : 7 0 7 . 'l-opogluPltit l-i.1. [-ittlc CB. (ihosh P. tsellengerC'R. r rLrnt i o r i ; 1 b i o l l c ' i 1 1a n c i r l c c o t i n \ \ l l t h ! ' \ i : h \ l r f l i ( L t l r re . l r l i l l r s cl n lha ùrrl\ \tl{e\ o l o s t c o l i r t l r r i t i s :\ n e t p t r i n r c ' n t r l s t u t i r i n ' h c . ' p . . l O r t h o p R r ' \ l ( ) ( ) ( r I: J : J . l . l + J . l 5 - 1 . l - i t t l c C ' . S n r i t h S . ( i h o ' h [ r . [ J e ] l r ' n g cC r '.Historlolpho l r r r i c a l r r r r l i n l n r r n L r l r i r l o e h c n t i eci l\ l l r l u . t t i o no l . j o i n t c h a n u c si n l r t n o r l c l o l o s l e r r r L r t h r i l i :i n t l u e c i l b r l a t c l a l n t c n i s c e c t o t r r r i n s h c c p . J R h c L r r t t r t L lr (l ) 9 7 : l - 1 : 1 1 9 9 - 1 0 9 . l-i5. Applr'rlLnl RC'. Cihosh P. Sluin N,lV. Biurtrechlnicri. h i \ t o l o c i c r l t L n r li n r n u n o h i r t o c h e n t i c a l s t u d i c s o f p l t e l l t l c l r t r lagc in rn i)\irrr' nlodel ol osleoarth|itis intlucctl bt late|ll r r c n i s c c c t o n r r . O s t e o l r t h f i l i s C a r t i l a g e 19 9 9 : 7 : l U l - 9 - + . 1 5 6 . B L r l k h a r c l tD . H u a S - Y . C i h o s h P . A n o r e l r t r i c n r a s s a v ti)r thc quilntitiition ol the sullutctl slVcosanlinogl\c:It content of histololliciil scctious: Its application to delernrine thc clJtcts of Dilcerhein on cartilagc in rn orinc rnodel of osteolrthrilis. ( J s t e o a f t h fi t i s C i a r t il a g e l ( X ) I : 9 : l l l J - 1 7 . l - 5 7 . H n a S - Y . B u r k h a r d t D . t - i t t l eC . G h o s h P . ' l h e e l l c c t s of orallV ildnrinistefe(lI)iacetein on cartilagr and sr:bchonilral I N T R A - A R T I C U L AH RY A L U R O N A NT H E R A P YI N O S T E O A R T H R I T I S b o n ei n a n o r i n e n . r o d eol t o s t c o a r t h r i t i sJ .R h e L r n t l t ol (l X ) l : 1 8 : 82-5-il. l 5 l J . S m i t h N ' l \ { . G h o s hP . I i x p c r - i r r c n t ar nl o d e l so l u s t c u a r t h r i t i s .I n : O s t c o a l t h r i t i sD. i a c n o s i sa n d N l c t l i c a l / S L r r - g N i c'a[ al n l u g c n l c nN t . l o s k o u , i t zR \ \ ' . H o \ c l l D S . ' \ l t r n l n R D . B u c k n a l t e r J A a n c lG o l t l b e r sV N , l .e d s . P h i l a d e . l p h i La o. n d o n .N e u Y o r k . S t . l . o u i s . S r d n e l ' . T o r o n t o : W B S a u n c l c r (si o n t p a n l 2 ( X ) l : l1 1-99. 1 5 9 . G h o s hP . R e a cR l . A n n s t r o n gS . H o l b e r tC . S u n D . H i g l r contact\tres\ incluccclbv nreniscectontrlcsults in ciLrtilil-l.tc tncl s y n o r i a l l l u i t l c h a n c c s c o n s i s t e n tu i t h c l u l r o \ t L ' ( ) i r r t h r i t i \ . T n u r : l n i l C o r n b \ 4 e e t i n gO r - t h o pR e s S o c . L S , \ . J i r p u n (. - . r n . an Dicgo.LISA lt)9-5:57. a d a . E L r r q r eS 1 6 0 . C a k e N { A . R e a dR A . G u i l k r L B r . (iho.h P. \lrrlillcrLtiun l onc Plrlhrilolr in lrn o f l t l t i c t t l a rc l t r t i l a g en n r l s u b c h o n d l u h o r i n c n t c n i s c c c t o t n tn' t o d e l o l o s t c r r a r l l t r i t ib: r r r o ù r r l o l r t r l s o ri t L t n r a p t t n i t i l i b(l A e sS l ' t . O r t c o r r t h r i t i (r ' r r t i l r L r tl ( ) 0 1 1:: f - 1 0 +I- l . l ( r l . C l h o s hP . X L r , \ . t l u i r S - \ ' . B L r l k h r L r Ir)l .r l - i t t l c C . É r a l L u L t i or lnc sc t t c t r r l c l r r t l i r e c r h é i ntcl a n r L r r lrt o d é 1 ci ,' r i n t l l i r t l r r o s e .l - r L R c r u c t l L r P l r t i c i c n t P . t l i s r 1 9 9 3 : - 1 8 : S lS- +. l 0 ( \ Ù p p )l . 1 ô 1 . C i h o s hl ' . \ \ ' c l l s ( 1 . N u n t a l uY . R c a c iR . . , \ r r l s t r o n cS . T h c c l f c c t s o f o r a l l v a d r n i n i s t e l c dt i a p r o l è n i cl c i d o n t l t e b i o s l ' n t h e s iosf p r o t c o u l l , c u ni sn e x v i t ' u c a r t i l u g ec u l t u r e sl i o r ) t . j o i n t so f a n i n r a l su i t h c u r l v o s t e o a r l h r i t i sC.L r r rT h e r R e s l 9 9 J : 5 - 1 : 7 0 .113- . 1 6 3 . G h o s hP . R e a c R l . A r n t s t r o l t !S . W i l s o n D . \ l r r s h a l l R . -['hc N'[cNaiP r . c f f e c t so l i r ] t r a - a r t i c u l iilrrc l n r i n i s t r e t i o n l hr.rl u r o n a ni n l n r o t l e lo l c a r l r o s t c o l r r t h r i tiins: h c c p . L C i l r i t a n a l r : i s t. i i l i i r l i r l i c l Ll rl n r l t o r p h o l o u i c trrtlL r t l i c S ' . e n t i r.r\ r t l t rt t i s R h e u n 1 9 9 - l : l l ( S u p p lI.r :l l t - . 1 0 . l 6 - 1 .C h o s hP . R e a dR . \ u n t i r t i r\ . S n t i t hS . \ r l t , l T r , n L\ . W i l s o nD . T h c c t l è et s o l i n t l t l t r i i eL i l r tr.r l n t i n t \ t f , 1 l j (\ ) l tl r . \ . 1 l u r t t r n ri n l t n r o d c o l l r - r r l \ ( ) \ 1 c ( ) r i r l h riint i.sh c c | . l l ( . 1 | t r l r r g c c o m p o s i t i o na n c l p r o t r ' o L l r c i t rnn e t r r b t r l i . nSt .c n t i n . \ r t h r j t r ' R h e u n rl 9 9 l : l l ( S u p p l . I t : - lI 1 1 . 1 6 5 . A l n i s t r o n gS . R c a d R . ( l l r o s h P . T h c c i l c e t s o t i n t l u l f t i c u l a r h t a l t r r o n n no n c a r t i l a g ci i n d s u b e h o n t l l ibr lo n cc h l n g c s in nn or ine moclco l l c a r l l o s t e o a r t h r i t i.sl .R I ) c L l l n u t ol 9l 9 . 1 t lI : 6u0-8. l 6 ( r . G h o s hP . H o l b e r tC . R c a dR . A r n t s t l o n gS . H v a l u r o n i e û c i c l( h v a l u r o n i l l l i)n c \ p e f i r n e n t a o l s t e o l r t h r i t i sJ. R h e L r n t a t o l I 9 9 5 : 1 2|:5 5 - 7 . 1 6 7 . G h o s h P . r \ r r r s t r o n gS . R c a d R . N u n t a t aY . S n r i t hS . N , l c N r r rP . e t u l . . A n i n r a m l o t l e l so f c a r l t o s t e o u r t h r i t i sf:h c i r u s e l b r t h e e r l i l L r l t i o no f p o t e n t i acl h o n d l o p r o l c c tci r. t ! l c l t t \ I. l t : J o i n t l ) c s t r u c t i o ni n A r t h r i t i s a n d O \ t c o a r t h f i t i sr.r n d c . rB c r g \ \ ' . ù r l . l O 0 . lÀ À \ l ( , 1 ( , - t - 1 { J ( \ . 1 6 8 . A d a n r N . S t u d r e so n h v l l u r o n a nu n d s l r c o s l n t i n o s l v c u n s o f n o r r n a l a n c l p a t h o l o g i c i r sl r n o r i a l l l L r i d . \ l a s t e r o l ' S c i e n c ei n N l e d i c i n cT h c s i s .U n i v c r r i t yo i S l , t l n e y1 9 9 9 . 1 6 9 . ( l h o s h P . K i p i c B . S q , a i nN l . S m i t hN I N I .C a k e N { .R e a c l R . I r r p r o v e r n e n itn r h e o l o - s i c apl a r i u l e t c r so f s v n o r i a l l l u i d s r s p i r a t e dt i o m O A . j o i n t so l ' s h e c pa d m i n i s t e r e idn t n r - a r t i c u l a r h v a l u r o n a n( N { W - 0 . 5 - 0 . 7 . 1X 1 0 6D l ) b u t r r o ta h i g h c r M W p r e p a r a t i o n(.s u b n r i t t e cl i lr r p u b l i c a t i o n ) : 3l 1 7 0 . H i r o t a W . I n t r a a r t i c t r l a ri n j e c t i o no t h v a l u r o n i cr c r c l l c c l u c e st o t a l a n r o u n t so l l e u k o t l i e n eC - , 1 .6 k e t o - p r o s t a g l a n d i n F l - a l p h a . p r o s t a r l a n c l i nF 2 a l p h a r n c l i n t e r l e u k i n - l b e t a i l s l n o r i a l l l u i d o l p a t i e n t sw i t h i n t e r n a .l l e r { n g e m e ni tn d i s o r d e r s o f t h e t e n r p o l o n r a n c l i b r - r l a r . j o1i n3 trJ. O r a l N ' l a r i l l o l a cS u r c l 9 9 t t : 1 6 : 3 85 . l 7 l . P u r r z Ii - . S c h i a ro n F . R a r r o n d aR . N 4 a l a t c sVt. G a n r b ; L i r P . T u t l e s c oS . I n t r l a r t i c u l a rh t , a l r - r r o nai c j d i n t h e t r e u t n r e nttl 1 i n f l a n r r n l t o r ta' n c ln o n i n l l a m r n a t o rkvn c c c l l u s i o n s .C u r r T h c r Resl9E3:-11:6-!l-7. l 7 l . P r r n zIi - . S c h i a r o nF . C l a r a s i F a . Ganrbrri n . R a r n o n dR P F . T o i l c : c o S . T h c i n t l L r c n cocf i n t r a - a r t i c u l ahrv a l u r o n i ca c i d L r nP ( i l : . : L n i e l . \ \ l P o l : r r t o r i l l f l u i d .( l l i n E x p R h e L r m a t o l I 9 S 9 : l : l1 r - 5 0 . l l . l . I ) t r L r r l r r l o\ 1. . \ r t n c n \ 1 . I . r s t r - a\ ,t. A l n r o r -B . H i g h n r o l c e L r l rur e l i c h t. L r t l i L r n h \ r l u r ( ) n l r t lùL I i r l e c t i n) i n o s t e o l r t h r i t i s o f t h c k n c c : . r o n c r c r r rp l r r c c b icr ( ) n t r ( ) l l ct(rli l l . O s t e o a r t h r j t i s C a r t i l r g cI 9 9 l : I : ( ) r -l 0 . l l 7 - 1 . C o r l l i k r E l \ 1 . P c l L r s o( i F . C i i c l i o t t iS . D e D u r l n t e C . Palmicri D. Savoit \1. ct al. Thc etIèctsol intra-irrliculrr a i l n r i n i s t r a t i o n1 ' t h eh r u l u r - o n iacc i d o n o s t c o a r t h r i toi sf t h c k n e e : a c l i n i c l l s t u d l ' * i t h i n r r r u n o l o g i c a ul n c l b i o c h e n r i c a l e v a l u u t i o n sE. L r r. l R h e u n r l t o lI n l l a n r m l 9 t ) 5 :I 5 : - 1 7 - - 5 6 . 1 7 5 . l \ { c n s i t i c r iN I . ; \ n r b r o s i o 1 . . l n n a c c S . P e r b e l l i n i A . N i c o l a i sl - . V i s c o e l a s t i ce r a l L r a t i o n o l ' d i l ' l è r e n tk n e e o s l e o a r t h l i t i s t h c r a p i c s..l N , l a tS c i N , l a tl \ l e - t l1 9 9 - 5 : 6 l i :0 7 . I 7 ( r . I - r ' i z z i c nLr . C o r o n i H . B l c e h i n i P . I n t n t a r t i c u l ahl y a l u r o n i e r r c i d i n t h c t r c r l r l e n t o l o : l c o a r l h r i t i so f t h c k n c c : ( ' l i n i i r r ll L n t nl ( r r n h o l ( ) r i u l' rt tl r t l r .( l i n E \ p R h e u n l r t o l 9 9 l l : l6:1il() l - - . ( l L r r l , , L Ii r) . I i r r rl : . ( i r r c r r iIr) . I ' i t s t l r r iR t loi n c h c t tI i. \ l 0 r l L r l . r l r r tr r lt r , \ 1 . ( , i r r l l l r i thi \r r o d i u l ] t h r r l r r r o n l r t ct:D 0 r .. \tL-oafil)riR t i \e I . h , ' l , , . l i . . Ll ll n L l i n - rl 'ro n r h u n r l n b i o p s i c - O ' t r r r e l rS r i ei c t r \ \ L r r k s h r ropn \ O a n c iC O X . I ; l o r e n c eO . ctobcr' l 5 - [ 1 ( ) 9 tl 9 9 l J : 1 7 3 . C i L r i d o l iD n D. PlscluulR i o n c h e t tE i . L i n i E . C i u e r r aI ) . [ ] r ' i z z i c l oL . N { o l p h o k r g i c nal n a l y s i so l a r t i c u l n rc a r l i l a g cb i o p s i e sf r o n r u n t n d o n r i z e cd l i r r i c a ls t u d vc o m p a r i n gt h c e l l c c t so l ' r v a l u r o n a t c( H y a l g a n lu n t l n r e t h r l p r e c l 5 ( X ) - 7 3 0k D a s o c l i u n h n i s o l r n eû c e t i l t eo n p r i n r a r vo s t e o i r r t h r i t oi sf t h c k n e e .O s l e o l t r t h l i t i sC a r - t i l r glc0 0 l : 9 : 3 7 18 L 1 7 9 . P r s q L r a lRi o n c h e t t Ii . G u e l l a D . T a p a r c l l iF . t s o r a l c lFi . B e r s a m i r l iG . N l o r i G . e t a l . \ ' l o r p l r o l o g i c aul n a l r : i s o l k n e c s v n o r i a l m c r n b r a n cb i o p s i c s l i o n r a n t n d o n r i z e dc o n t r o l l e t l c l i n i c a l s t u c l l 'c o r n p a r i n - tl th c c t ' f f c t s o f s o d i u l n h r a l u r o n a t e ( H y a l g a n ) a n d r r e t h v l p r e d n i s o k r nlec ù t a l c ( I ) c p o n t c c l - o l i)n o s t e o a r t h r i t i sR. h e L r n r r t o l o gl (r X ) l : - 1 0l :- : t - 6 9 . 1 8 0 . L i s t r a tV . A r l u l X . f ' a t t l n e l l oF . B o n v u l c t . l P . S i r n o n n c t J . A n r o l B . e t i i l . . \ r t h r o s c o p i ce l a l u a t i o n o f p o t c n t i a l s t r ù c t L l rner o t l i l rr n g a c t i \i t ) ' o f h v a l u r o n a n( H V a l g a n )i n o s t e o a f i h r i t i so f t h e k n e e .O s t e o a r t h r i t iC s a r t i l a g c1 9 9 7 : 5 : 1 5 3 fi1. l 8 l . . l L r bR b W . P i r a S . B e i n a tL . D a r c r e . lG . i s h e nP . S t r u c ture ntoclillcation i n o s t c u a r t h r i t i us i t h i n t r a a r t i c u l a rs o d i u r r r hvalunrnate o T r n o l e c u l aur e i g h t o 1 5 0 0 - 7 3 0k D a . A n n R h e u r n D i s 2 ( X |) : 6 0 : . 1 6 .
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