A Wnt/β-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes.
OBJECTIVE
The results of recent animal studies suggest that activation of Wnt/β-catenin signaling in articular chondrocytes might be a driving factor in the pathogenesis of osteoarthritis (OA) by stimulating, for instance, the expression of matrix metalloproteinases (MMPs). The aim of this study was to investigate the role of Wnt/β-catenin signaling in interleukin-1β (IL-1β)-induced MMP expression in human chondrocytes.


METHODS
Primary cultures of human, murine, and bovine articular chondrocytes as well as human mesenchymal stem cells and mouse embryonic fibroblasts were used in the experiments. Multiple strategies for the activation and inhibition of signaling pathways were utilized. Reporter assays and coimmunoprecipitation were performed to study the interaction between β-catenin and NF-κB.


RESULTS
In contrast to the role of Wnt/β-catenin in animal chondrocytes, in human chondrocytes it was a potent inhibitor of MMP-1, MMP-3, and MMP-13 expression and generic MMP activity both in basal conditions and after IL-1β stimulation. This effect was independent of the T cell factor/lymphoid enhancer factor family of transcription factors but rather was attributable to an inhibitory protein-protein interaction between β-catenin and NF-κB. IL-1β indirectly activated β-catenin signaling by inducing canonical Wnt-7B expression and by inhibiting the expression of canonical Wnt antagonists.


CONCLUSIONS
Wnt/β-catenin signaling in human chondrocytes had an unexpected anticatabolic role by counteracting NF-κB-mediated MMP expression induced by IL-1β in a negative feedback loop.
University of Twente, Enschede, The Netherlands.
Bin
B
Ma
Clemens A
CA
van Blitterswijk
Marcel
M
Karperien
D000368:Aged; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
D007375:Interleukin-1; D016328:NF-kappa B; C490675:WNT7B protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1