Small molecule inhibitors of WNT/?-catenin signaling block IL-1?- and TNF?-induced cartilage degradation.

ABSTRACT: INTRODUCTION: In this study, we tested the ability of small molecule inhibitors of WNT/?-catenin signaling to block interleukin 1? (IL-1?)- and tumor necrosis factor ? (TNF?)-induced cartilage degradation. Proinflammatory cytokines such as IL-1? and TNF? are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/?-catenin signaling was found to be involved in IL-1?- and TNF?-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/?-catenin signaling might block IL-1?- and TNF?-induced cartilage degradation. We tested the effect of small molecules that block the interaction between ?-catenin and TCF/Lef transcription factors on IL-1?- and TNF?-induced cartilage degradation in mouse fetal metatarsals. METHODS: We used mouse fetal metatarsals treated with IL-1? and TNF? as an ex vivo model for cytokine-induced cartilage degradation. Metatarsals were treated with IL-1? and TNF? in combination with the small molecules PKF115-584, PKF118-310 and CGP049090 at different concentrations and then harvested them for histological and gene expression analysis. RESULTS: We found that IL-1?- and TNF?-induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/?-catenin signaling using small molecule PKF115-584 and partially using CGP049090 dose-dependently. In addition, we found that PKF115-584 blocked IL-1?- and TNF?-induced MMP mRNA expression, but did not reverse the inhibitory effect of IL-1? on the expression of cartilage anabolic genes. CONCLUSION: In this study, we show that inhibition of WNT/?-catenin signaling by small molecules can effectively prevent IL-1?- and TNF?-induced cartilage degradation by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/?-catenin signaling in IL-1?- and TNF?-induced cartilage degradation.

SUBMITTER: Landman EB 

PROVIDER: S-EPMC3978727 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature