Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1.
OBJECTIVE
Wnt signaling pathway proteins are involved in embryonic development of cartilage and bone, and, interestingly, developmental processes appear to be recapitulated in osteoarthritic (OA) cartilage. The present study was undertaken to characterize the expression pattern of Wnt and Fz genes during experimental OA and to determine the function of selected genes in experimental and human OA.


METHODS
Longitudinal expression analysis was performed in 2 models of OA. Levels of messenger RNA for genes from the Wnt/beta-catenin pathway were determined in synovium and cartilage, and the results were validated using immunohistochemistry. Effects of selected genes were assessed in vitro using recombinant protein, and in vivo by adenoviral overexpression.


RESULTS
Wnt-induced signaling protein 1 (WISP-1) expression was strongly increased in the synovium and cartilage of mice with experimental OA. Wnt-16 and Wnt-2B were also markedly up-regulated during the course of disease. Interestingly, increased WISP-1 expression was also found in human OA cartilage and synovium. Stimulation of macrophages and chondrocytes with recombinant WISP-1 resulted in interleukin-1-independent induction of several matrix metalloproteinases (MMPs) and aggrecanase. Adenoviral overexpression of WISP-1 in murine knee joints induced MMP and aggrecanase expression and resulted in cartilage damage.


CONCLUSIONS
This study included a comprehensive characterization of Wnt and Frizzled gene expression in experimental and human OA articular joint tissue. The data demonstrate, for the first time, that WISP-1 expression is a feature of experimental and human OA and that WISP-1 regulates chondrocyte and macrophage MMP and aggrecanase expression and is capable of inducing articular cartilage damage in models of OA.
Blom
Arjen B
AB
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. a.blom@reuma.umcn.nl
Brockbank
Sarah M
SM
van Lent
Peter L
PL
van Beuningen
Henk M
HM
Geurts
Jeroen
J
Takahashi
Nozomi
N
van der Kraan
Peter M
PM
van de Loo
Fons A
FA
Schreurs
B Wim
BW
Clements
Kristen
K
Newham
Peter
P
van den Berg
Wim B
WB
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism*; D055511:CCN Intercellular Signaling Proteins; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology; D010450:Endopeptidases / Q000096:biosynthesis; D015870:Gene Expression; D006614:Hindlimb / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015207:Osteoarthritis, Hip / Q000235:genetics / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D013583:Synovial Membrane / Q000378:metabolism
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C492067:CCN4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D010450:Endopeptidases; D020782:Matrix Metalloproteinases; C083641:aggrecanase