Small molecule inhibitors of WNT/ß-catenin signaling block IL-1ß- and TNFα-induced cartilage degradation.
Arthritis Res Ther
; 15(4): R93, 2013 Aug 21.
Article
de En
| MEDLINE
| ID: mdl-23965253
ABSTRACT
INTRODUCTION:
In this study, we tested the ability of small molecule inhibitors of WNT/ß-catenin signaling to block interleukin 1ß (IL-1ß)- and tumor necrosis factor α (TNFα)-induced cartilage degradation. Proinflammatory cytokines such as IL-1ß and TNFα are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/ß-catenin signaling was found to be involved in IL-1ß- and TNFα-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/ß-catenin signaling might block IL-1ß- and TNFα-induced cartilage degradation. We tested the effect of small molecules that block the interaction between ß-catenin and TCF/Lef transcription factors on IL-1ß- and TNFα-induced cartilage degradation in mouse fetal metatarsals.METHODS:
We used mouse fetal metatarsals treated with IL-1ß and TNFα as an ex vivo model for cytokine-induced cartilage degradation. Metatarsals were treated with IL-1ß 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-1ß- and TNFα-induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/ß-catenin signaling using small molecule PKF115-584 and partially using CGP049090 dose-dependently. In addition, we found that PKF115-584 blocked IL-1ß- and TNFα-induced MMP mRNA expression, but did not reverse the inhibitory effect of IL-1ß on the expression of cartilage anabolic genes.CONCLUSION:
In this study, we show that inhibition of WNT/ß-catenin signaling by small molecules can effectively prevent IL-1ß- and TNFα-induced cartilage degradation by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/ß-catenin signaling in IL-1ß- and TNFα-induced cartilage degradation.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Pérylène
/
Arthrite
/
Cartilage
/
Voie de signalisation Wnt
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Arthritis Res Ther
Sujet du journal:
REUMATOLOGIA
Année:
2013
Type de document:
Article