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Original Hypothesis
Osterix combined with gene-activated matrix:
A potential integrated strategy for achieving
cementum regeneration
Rubing Liu1,3, Zhengguo Cao1,2
Department of Periodontology, The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST KLOS) and Key Laboratory
for Oral Biomedical Engineering of Ministry of Education, 2Department of Periodontology, School and Hospital of Stomatology, Wuhan University,
Wuhan, 3Department of Periodontology, the Affiliated Hospital of Stomatology, College of Medicine, Zhejiang University, Hangzhou, China
1
A B S T R A C T
Introduction: Human periodontitis is the most common infectious disease that results in the destruction of periodontal supporting
tissues including the root cementum. Currently cementum regeneration, as a vital event, is considered as a gold standard of successful
periodontal tissue reconstruction. Nevertheless, one of the important requirements of cementum reestablishment is the recruitment
and differentiation of pre-cementoblasts into functional cementoblasts, which requires effective regulator factors. Recently, Osterix
(Osx) is known to be a key transcriptional factor essential for osteogenesis and especially for cementogenesis. Although there are
various interesting approaches involving tissue engineering, gene-activated matrix (GAM) is one of the most promising approaches
to achieve reliable restoration of the periodontium. The Hypothesis: Based on the recent advances in understanding the mechanisms
of Osx in cementum development and formation, we hypothesize that Osx plays a critical role in periodontal regeneration and Osx
combined with GAM may be an effective strategy for the regeneration of cementum. Evaluation of the Hypothesis: Osx combined
with GAM could pave the way for the development of new tissue engineering procedures and have the potential to play a pivotal
role in cementum regeneration, eventually increasing the predictability of periodontal tissue regeneration.
Key words: Cementogenesis, gene-activated matrix, osterix, periodontal tissue engineering
Introduction
Human periodontitis is a common infectious disease
and contributes to the destruction of periodontal
supporting tissues including the cementum and
ultimately leads to tooth loss if it is not adequately
treated.[1] Currently, periodontal tissue engineering is an
emerging multidisciplinary field and can be advanced
by the gene-activated matrix (GAM) technology which
combines tissue engineering and gene delivery system
strategies.[2-5] It is well known that the gold standard
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DOI:
10.4103/2155-8213.150864
of periodontal regeneration is functional cementum
reestablishment.[6] The regeneration of cementum
contains many events, [7] including the migration
and attachment of cementoblasts to the appointed
position, proliferation and differentiation of cells,
matrix biosynthesis and mineralization. All these
require numerous growth factors and transcriptional
factors including Osterix (Osx).[7,8]
Essential role of Osx in bone formation and
cementogenesis, as an important transcriptional
factor
Osx, also named Sp7, is a transcriptional factor
for osteoblast differentiation and participates in
mineralization.[9-11] In 2002, Osx was firstly identified as a
bone morphogenetic protein-2 inducible gene in the mice
C2C12 skeletal muscle cells.[10] Osx acts as a downstream
gene of Runx2.[10,12,13] During bone formation, osteoblast
differentiation from mesenchymal stem cells occurs
Corresponding Author: Dr. Zhengguo Cao, Department of Periodontology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
E-mail: [email protected]
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Liu and Cao: Osterix and cementum regeneration
through a multistep molecular pathway regulated by
various signaling proteins and transcriptional factors,
including Ihh, Wnt, and FGF families as well as Pax,
Hox, bHLH, Runx2, and Osx, which outline the threedimensional information that determines the shape of
mesenchymal condensations.[14,15]
Osx is required for osteoblast differentiation. It has
been demonstrated that Osx is essential for osteoblast
differentiation in vivo and vitro[10,16-18] as well as in
embryos[10] and postnatal mice.[19] During the process
of osteogenesis, there are several bone related genes
which are responsible for the deposition and maturation
of bone extracellular matrix, such as BSP, OCN, OPN,
and ALP.[20-23] In Osx null mutant embryos, which die at
birth, no bone formation takes place in the endochondral
membranous skeleton. Those bone related genes are all
absent in the condensed mesenchyme of membranous and
endochondral skeletal elements.[10] Therefore we conclude
that Osx promotes the differentiation of osteoblasts.
Runx2 and Osx were co-localized in cementoblasts,
and Osx was significantly upregulated in cementum
on both compression and tension sides during the
orthodontic tooth movement. [9,24] Specifically, our
recent studies showed that there is a close relationship
between a temporal- and spatial-expression pattern
of Osx and formation of cellular cementum, and
an accelerated cementum formation in the 3.6-Col
1-Osx transgenic mouse line. On the other hand,
conditional deletion of Osx in mesenchymal cells by
crossing the 2.3 kb Col 1-Cre and Osx loxP mice led
to a sharp reduction in cellular cementum formation
(including cementum mass and mineral deposition
rate), [8] suggesting that Osx may be required for
cementoblasts differentiation. Jin et al.,[25] conducted
cementum engineering with cloned cementoblasts
(OCCMs) combined with three-dimensional poly
lactic-co-glycolic acid (PLGA) scaffolds and detected
the gene expression of type I collagen, OCN, and
BSP in OCCM-seeded PLGA scaffolds. Furthermore,
when cementoblasts were transiently transfected with
PEX3-Osterix plasmid, significantly higher transcript
level of BSP, OCN, and ALP was observed. So we can
confirm that Osx does exist and functionally operate
in cementogenesis.
The Hypothesis
Human periodontitis would often result in tooth loss
ultimately, if there were no adequate and effective
treatments. This tragedy will undoubtedly exert
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significant impact on the patient’s quality of life. Hope
is, as expected, pinned on periodontal tissue engineering
with the help of gene-activated matrix (GAM) technology.
Furthermore, emerging reports have demonstrated the
express of osteogenic transcriptional factor Osx and
its vital function in cementogenesis.[8,9,24] Based on the
common characteristics between cementum and bone
as well as the recent advances of osterix in cementum
formation, we make the following hypothesis.
Possible role of Osx in cementum regeneration
Although cementum differs from bone in its
histological profile by lacking innervation and
vascularization, and has limited remodeling potential,
it is very similar to bone. Cementum seems to contain
elements in common with those associated with
bone and be developmentally controlled by similar
factors.[26] These factors may regulate differentiation
and proliferation of cementoblasts and deposition
of cementum matrix. Cementum is consisted of
approximately 50% hydroxyapatite and 50% collagen
and non-collagenous proteins. [27] We have also
discussed the existence of Osx in cementum and
its potential role in cementum development via
controlling the proliferation and differentiation of
cementoblasts. As it is known, the process of tissue
engineering is imitating that of embryogenesis and
morphogenesis involved in the original formation of
the tissue. Moreover, in a tissue engineering biology
model, bone regeneration is driven by transcriptional
factors Osx, which responds to released BMP2.[28] So
Osx may play a positive role in periodontal tissue
engineering.
The key event in periodontal tissue regeneration is the
attachment of connective tissue fibers (Sharpey’s fibers)
to the hard tissues (bone and cementum).[6] Cementoblasts
are responsible for laying down cementum on the root
surface. It is clear that types I collagen, OCN, and BSP
are essential for cementum mineralization[27,29-30] and
are able to be upregulated by Osx,[10] so the process
of cementum regeneration maybe impossibly occur
without the Osx. And for this reason, we postulated
that Osx might play a potential role in cementoblasts
differentiation and serve as a possible positive regulator
for matrix mineralization in the process of cementum
reconstruction.
Osterix combined with GAM: A potential integrated
strategy for achieving cementum regeneration
Recently, more attention has been paid to geneactivated matrix (GAM) in periodontal tissue
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Liu and Cao: Osterix and cementum regeneration
regeneration. A novel GAM with embedded chitosan/
plasmid nanoparticles encoding PDGF based on
porous chitosan/collagen composite scaffold has
been developed. This scaffold provides a nonviral vector to condense DNA and serves as an
effective kind of material for PDLCs adherence and
proliferation. [5] On the other hand, the DNA can
also be encapsulated by cationic liposome [31] to
form lipoplexes, which is capable to locally express
the relevant regulatory factors in the process of
periodontal regeneration. The feasible combination
of effective Osx and liposome or scaffold material
indicates that the novel GAM strategy with Osx has
a promising role in the application of periodontal
tissue regeneration, especially in the reconstruction
of cementum.
3.
Evaluation of the Hypothesis
10.
It is obvious that significant progress has occurred
in the field of periodontal tissue engineering at the
preclinical level during the past decades. Meanwhile,
the study of signaling pathway associated with the
proliferation and differentiation of cementoblasts is
and will always be the hot topic among researchers
and will lead to the generation of new knowledge
about cementum regeneration. Undoubtedly Osx, as
a potential factor in development and regeneration
of cementum, will pave the way for the development
of new tissue engineering procedures needed for
the predictable regeneration of periodontal tissues.
Taken together, we believe Osx combined with GAM
could actually play a pivotal role in cementum and
the other periodontal tissue regeneration methods
including alveolar bone and periodontal ligament,
and eventually improves the quality of life of
patients.
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Acknowledgements
18.
The study has been supported by grants from the National
Natural Science Foundation of China (81170933 to ZC). All
the authors don’t have any conflict of interest.
19.
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Cite this article as: Liu R, Cao Z. Osterix combined with gene-activated
matrix: A potential integrated strategy for achieving cementum regeneration.
Dent Hypotheses 2015;6:10-3.
Source of Support: Nil, Conflict of Interest: None declared.
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