Original Article Orthopedics and Rheumatology What is the Etiopathogenesis of OA? Ahmad Javaid A lthough osteoarthritis (OA) is a disease of the whole joint, the primary change is loss of articular cartilage. Bony remodeling, osteophyte formation and synovial, capsular, ligamentous and muscular changes are secondary.1 The key to healthy hyaline cartilage is the maintenance of the architecture and composition of the extracellular matrix (ECM), under the control of highly specialized cells, the chondrocytes. However, these cells are sparse and isolated, accounting for only 1% of cartilage volume. The matrix consists of a structural framework of macromolecules and tissue fluid. The former are the collagens, proteoglycans and noncollagenous proteins and glycoproteins. The tissue fluid contains water (80% wet weight of cartilage), small proteins, metabolites and a high concentration of cations that balance the negatively charged proteoglycans. The collagens form a fibrillar mesh that gives the cartilage its morphology and provides protection against tension and shear. There are two major classes of proteoglycan (polysaccharideprotein conjugate) in cartilage, namely large aggregating molecules (aggrecan) and smaller nonaggregating molecules, such as decorin, biglycan and fibromodulin. The aggrecan molecule contains a central core protein with approximately 100 glycosaminoglycan (GAG, polysaccharide chains consisting of repeating disaccharides, which contain an amino sugar) sidechains of chondroitin sulfate and keratan sulfate, each of which contains 80-100 negatively-charged groups. The aggrecan molecules form proteoglycan aggregates by linking with a long central hyaluronan molecule, resulting in a very large complex with several hundred thousand fixed, negatively charged groups. The loss of articular cartilage in OA may start as a focal lesion and progressively extend to involve specific joint compartments, thus inducing alterations in articulating surfaces2 and leading to progressive loss of cartilage3 Batth Bone Joint Clinic Manual Medicine Ergonomics Orthopedic Specialist Spine and RSI Specialist Clinical Ergonomics Bangalore, Karnataka 748 Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013 Superficial fibrillation is associated with the loss of the small proteoglycans, decorin and biglycan, which are usually closely associated with the fibrils at the articular surface4 and the large proteoglycan aggrecan.5 Associated with the loss of these molecules, is an increased cleavage of type II collagen by collagenase,6 aggrecan cleavage7-9 and the degradation of small proteoglycans.10 Since, the degradation of the ECM exceeds its synthesis, there is a net decrease in the amount of cartilage matrix or even the complete erosion of the cartilage overlying the bone at the joint surface. This is thought to be caused by the increased proteolytic enzyme activity of the matrix metalloproteinases (MMP). The role of MMPs in the excessive matrix degradation that characterizes the cartilage degeneration of OA11 is supported by the increased expression of several MMPs in the cartilage of OA patients (e.g., MMP-3, MMP-13 and MMP-14). Recently, a group of MMP, called ‘aggrecanases,’ have been identified which are thought to play a major role in the breakdown of aggrecan (ADAMTS-1, ADAMTS-4 and ADAMTS-5).12 As the disease progresses, the local pH of the cartilage may fall and cathepsin B, cathepsin L and cathepsin K from the chondrocytes may participate in further cartilage destruction.13,14 A deficiency in the tissue inhibitors of MMP (TIMPs)15 clearly favors the excessive proteolysis seen in the diseased articular cartilage. It is thought that cytokines produced by the synovium and chondrocytes, especially interleukin (IL)-1 and tumor necrosis factor-a (TNF-a), play a significant role in the degradation of cartilage16 though prostaglandins (PG) and leukotrienes may also be involved. PGE2 is found to be increased in human OA-affected cartilage and reduces cell development and the induction of apoptotic processes in articular chondrocytes.17 The production of nitric oxide (NO), which is stimulated by proinflammatory cytokines, is involved in cartilage catabolism18 and also may induce the apoptosis of chondrocytes.19 The NO and PGE2 produced by activated chondrocytes in diseased cartilage may modulate disease progression in OA and should Orthopedics and Rheumatology therefore be considered potential targets for therapeutic interventions.17 It is accepted that there is at least some synovitis in established OA.20 Inflammation may start earlier in post-traumatic OA; here, the synovial fluid concentration of MMP, such as stromelysin-1 (which is more likely to be derived from activated synovial cells than cartilage), rapidly increases. Like many other cells in the body, synovial cells actively synthesize and secrete hyaluronic acid (HA, hyaluronan), and the size of HA molecules and their concentration in synovial fluid decrease in OA.21 Similarly, the levels of cartilage oligomeric protein, which is synthesized by synovial cells and chondrocytes, are increased in patients with accelerated large joint degeneration.22 These associations suggest that joint inflammation may accelerate joint damage. C-reactive protein levels may be modestly raised in the serum of patients with OA.23 References 1. Buckwalter JA, Mankin HJ, Grodzinsky AJ. Articular cartilage and osteoarthritis. Instr Course Lect 2005;54:46580. 2. Lohmander LS, Lark MW, Dahlberg L, et al. Cartilage matrix metabolism in osteoarthritis: markers in synovial fluid, serum and urine. Clin Biochem 1992;25(3):167-74. 3. Dieppe P, Cushnaghan J, Young P, et al. Prediction of the progression of joint space narrowing in osteoarthritis of the knee by bone scintigraphy. 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Myers SL, Brandt KD, Ehlich JW, et al. Synovial inflammation in patients with early osteoarthritis of the knee. J Rheumatol 1990;17(12):1662-9. 21. Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther 2003;5(2):54-67. 22. Vilim V, Olejarova M, Machacek S, et al. Serum levels of cartilage oligomeric matrix protein (COMP) correlate with radiographic progression of knee osteoarthritis. Osteoarthritis Cartilage 2002;10(9):707-13. 23. Sharif M, Elson CJ, Dieppe PA, et al. Elevated serum C-reactive protein levels in osteoarthritis. Br J Rheumatol 1997;36(1):140-1. ■■■■ Indian Journal of Clinical Practice, Vol. 23, No. 11, April 2013 749