[HTML][HTML] Small molecule inhibitors of WNT/β-catenin signaling block IL-1β-and TNFα-induced cartilage degradation

EBM Landman, RL Miclea, CA van Blitterswijk… - Arthritis research & …, 2013 - Springer
EBM Landman, RL Miclea, CA van Blitterswijk, M Karperien
Arthritis research & therapy, 2013Springer
Introduction In this study, we tested the ability of small molecule inhibitors of WNT/β-catenin
signaling to block interleukin 1β (IL-1β)-and tumor necrosis factor α (TNFα)-induced
cartilage degradation. Proinflammatory cytokines such as IL-1β and TNFα are potent
inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP)
expression and activity. Because WNT/β-catenin signaling was found to be involved in IL-1β-
and TNFα-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/β …
Introduction
In this study, we tested the ability of small molecule inhibitors of WNT/β-catenin signaling to block interleukin 1β (IL-1β)- and tumor necrosis factor α (TNFα)-induced cartilage degradation. Proinflammatory cytokines such as IL-1β and TNFα are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/β-catenin signaling was found to be involved in IL-1β- and TNFα-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/β-catenin signaling might block IL-1β- and TNFα-induced cartilage degradation. We tested the effect of small molecules that block the interaction between β-catenin and TCF/Lef transcription factors on IL-1β- and TNFα-induced cartilage degradation in mouse fetal metatarsals.
Methods
We used mouse fetal metatarsals treated with IL-1β and TNFα as an ex vivo model for cytokine-induced cartilage degradation. Metatarsals were treated with IL-1β and TNFα 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-1β- and TNFα-induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/β-catenin signaling using small molecule PKF115-584 and partially using CGP049090 dose-dependently. In addition, we found that PKF115-584 blocked IL-1β- and TNFα-induced MMP mRNA expression, but did not reverse the inhibitory effect of IL-1β on the expression of cartilage anabolic genes.
Conclusion
In this study, we show that inhibition of WNT/β-catenin signaling by small molecules can effectively prevent IL-1β- and TNFα-induced cartilage degradation by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/β-catenin signaling in IL-1β- and TNFα-induced cartilage degradation.
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