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Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis


Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis1,2, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen–producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4–specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage destruction in both syndecan-4–deficient mice and syndecan-4–specific antibody–treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.

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Figure 1: Expression of syndecan-4 in human, rat and mouse is upregulated in osteoarthritic chondrocytes and correlates with the progression of the disease.
Figure 2: Deletion of syndecan-4 protects osteoarthritic cartilage from proteoglycan loss that is accompanied by reduced aggrecan neoepitope staining.
Figure 3: Injection of syndecan-4–specific antibodies into osteoarthritic knees of WT mice protects from proteoglycan loss that is accompanied by reduced aggrecan neoepitope staining.
Figure 4: The activation of ADAMTS-5 depends on its direct interaction with syndecan-4 and on syndecan-4–regulated MMP-3 expression and activity.


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We would like to thank A. Forsberg, S. Niehues, S. Ecklebe and K. Reher for technical assistance. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Pa689/7-1 to T.P. and F.E. and Th667/6-1 to G.T. and C.H.), the Collaborative Research Centres (SFB 492; project B18 to R.D. and B19 to T.P.) and Deutsche Arthrosehilfe e.V (p77-a117-Rüther-EP2-fuer1-knie-ko—49k-2006-7 to M.F.).

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Authors and Affiliations



F.E. designed and performed all Sdc4−/− experiments and wrote the manuscript; J.B. performed all anti-Sdc4-Ab and Mmp3 inhibition experiments; R.D. performed collagen X stainings and northern blot experiments; I.M. performed the surgical induced osteoarthritis in the mice; K.N. performed syndecan-4–specific antibody injections and the MAPK assays; M.F. provided the human osteoarthritis samples; Y.J.L. and Y.W.S. provided the rat osteoarthritis model; C.H. performed the real-time gene expression experiments; G.T. participated in evaluating the data; and T.P. participated in data analysis, directed the project and wrote the manuscript.

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Correspondence to Frank Echtermeyer or Thomas Pap.

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Echtermeyer, F., Bertrand, J., Dreier, R. et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med 15, 1072–1076 (2009).

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