Small molecule inhibitors of WNT/β-catenin signaling block IL-1β- and TNFα-induced cartilage degradation
Arthritis Research & Therapy 2013, 15:R93 doi:10.1186/ar4273Published: 21 August 2013
Introduction In this study, we tested the ability of small molecule inhibitors of WNT/beta-catenin signaling to block IL1beta/TNFalpha induced cartilage degradation. Pro-inflammatory cytokines like IL1beta and TNFalpha are potent inducers of cartilage degradation by up-regulating MMP expression and activity. Since WNT/beta-catenin signaling was found to be involved in IL1beta/TNFalpha induced upregulation of MMP activity, we hypothesized that inhibition of WNT/beta-catenin signaling might block IL1beta/TNFalpha induced cartilage degradation. We tested the effect of small molecules that block the interaction between beta-catenin and TCF/LEF transcription factors on IL1beta/TNFalpha induced cartilage degradation in mouse fetal metatarsals. Methods We used mouse fetal metatarsals treated with IL1beta and TNFalpha as an ex vivo model for cytokine induced cartilage degradation. Metatarsals were treated with IL1beta and TNFalpha in combination with small molecules PKF115-584, PKF118-310 and CGP049090 at different concentrations and harvested for histology and gene expression analysis. Results We found that IL1beta/TNFalpha induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/beta-catenin signaling using small molecules PKF115-584 and partially using CGP049090, dose-dependently. In addition, we found that PKF115-584 blocked IL1beta and TNFalpha induced MMP mRNA expression, but did not reverse the inhibitory effect of IL1beta on the expression of cartilage anabolic genes. Conclusion In this study, we showed that inhibition of WNT/beta-catenin signaling by small molecules can effectively prevent IL1beta/TNFalpha induced cartilage degradation, by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/beta-catenin signaling in IL1beta/TNFalpha induced cartilage degradation.