Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis.
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Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. / Echtermeyer, Frank; Bertrand, Jessica; Dreier, Rita; Meinecke, Ingmar; Neugebauer, Katja; Fuerst, Martin; Lee, Yun Jong; Song, Yeong Wook; Herzog, Christine; Theilmeier, Gregor; Pap, Thomas.
In: NAT MED, Vol. 15, No. 9, 9, 2009, p. 1072-1076.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis.
AU - Echtermeyer, Frank
AU - Bertrand, Jessica
AU - Dreier, Rita
AU - Meinecke, Ingmar
AU - Neugebauer, Katja
AU - Fuerst, Martin
AU - Lee, Yun Jong
AU - Song, Yeong Wook
AU - Herzog, Christine
AU - Theilmeier, Gregor
AU - Pap, Thomas
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 15
SP - 1072
EP - 1076
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 9
M1 - 9
ER -
