1. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis.
- Author
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Echtermeyer, Frank, Bertrand, Jessica, Dreier, Rita, Meinecke, Ingmar, Neugebauer, Katja, Fuerst, Martin, Lee, Yun Jong, Song, Yeong Wook, Herzog, Christine, Theilmeier, Gregor, and Pap, Thomas
- Subjects
OSTEOARTHRITIS ,METALLOPROTEINASES ,THROMBOSPONDINS ,PROTEOGLYCANS ,PROTEIN kinases ,EXTRACELLULAR matrix proteins ,LABORATORY mice - 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 osteoarthritis, 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. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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