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

Nat Med. 2009 Sep;15(9):1072-6. doi: 10.1038/nm.1998. Epub 2009 Aug 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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