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

Nature Medicine volume 15, pages 1072–1076 (2009)Cite this article

Abstract

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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Acknowledgements

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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Author notes

  1. Frank Echtermeyer and Jessica Bertrand: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Medical University Hannover, Hannover, Germany

    Frank Echtermeyer, Christine Herzog & Gregor Theilmeier

  2. Institute of Experimental Musculoskeletal Medicine, University Hospital Munster, Munster, Germany

    Jessica Bertrand, Ingmar Meinecke, Katja Neugebauer & Thomas Pap

  3. Institute for Physiological Chemistry and Pathobiochemistry, University Hospital Munster, Munster, Germany

    Rita Dreier

  4. Department of Trauma, Hand and Reconstructive Surgery, University Hospital Munster, Munster, Germany

    Ingmar Meinecke

  5. Department of Orthopedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Martin Fuerst

  6. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Yun Jong Lee & Yeong Wook Song

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  1. Frank Echtermeyer
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Contributions

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.

Corresponding authors

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). https://doi.org/10.1038/nm.1998

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