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

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.

• Authors: Frank Echtermeyer, Jessica Bertrand, Rita Dreier, Ingmar Meinecke, Katja Neugebauer, Martin Fuerst, Yun Jong Lee, Yeong Wook Song, Christine Herzog, Gregor Theilmeier, Thomas Pap
• Journal: Nature medicine (Nat Med) Vol. 15 Issue 9 Pg. 1072-6 (Sep 2009) ISSN: 1546-170X [Electronic] United States
• PMID: 19684582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type X
• RNA, Messenger
• SDC4 protein, human
• Sdc4 protein, mouse
• Sdc4 protein, rat
• Syndecan-4
• ADAM Proteins
• ADAMTS5 Protein
• ADAMTS5 protein, human
• Adamts5 protein, mouse
• Matrix Metalloproteinase 3
• Mmp3 protein, mouse

Topics

• ADAM Proteins (genetics, physiology)
• ADAMTS5 Protein
• Animals
• Cartilage (pathology)
• Chondrocytes (pathology, physiology)
• Collagen Type X (biosynthesis)
• Disease Models, Animal
• Humans
• MAP Kinase Signaling System
• Matrix Metalloproteinase 3 (deficiency, genetics, physiology)
• Mice
• Mice, Knockout
• Osteoarthritis (etiology, pathology, physiopathology)
• RNA, Messenger (genetics, metabolism)
• Rats
• Syndecan-4 (antagonists & inhibitors, deficiency, genetics, physiology)