Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis.
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.
Echtermeyer
Frank
F
Department of Anesthesiology and Intensive Care Medicine, Medical University Hannover, Hannover, Germany. echtermeyer.frank@mh-hannover.de
Bertrand
Jessica
J
Dreier
Rita
R
Meinecke
Ingmar
I
Neugebauer
Katja
K
Fuerst
Martin
M
Lee
Yun Jong
YJ
Song
Yeong Wook
YW
Herzog
Christine
C
Theilmeier
Gregor
G
Pap
Thomas
T
D051722:ADAM Proteins / Q000235:genetics / Q000502:physiology*; D000071116:ADAMTS5 Protein; D000818:Animals; D002356:Cartilage / Q000473:pathology; D019902:Chondrocytes / Q000473:pathology / Q000502:physiology; D024121:Collagen Type X / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D020935:MAP Kinase Signaling System; D019278:Matrix Metalloproteinase 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D053671:Syndecan-4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D024121:Collagen Type X; D012333:RNA, Messenger; C508304:SDC4 protein, human; C508306:Sdc4 protein, mouse; C508307:Sdc4 protein, rat; D053671:Syndecan-4; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; C498489:Adamts5 protein, mouse; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse
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