| |
[摘要]：Chondrocytes, a unique cell type in cartilage tissue, are responsible for the regulation of anabolic and catabolic homeostasis in cartilage-specific extracellular matrix synthesis. Activation of Wnt/beta-catenin signaling induces dedifferentiation of articular chondrocytes, resulting in suppression of type II collagen expression. Wehave shown previously that beta-catenin inhibits beta-catenin-Tcf/Lef (T-cell factor/lymphoid-enhancing factor) transcriptional activity in articular chondrocytes with a concomitant recovery of type II collagen expression. In the current study, we elucidated the mechanism underlying this inhibition of beta-catenin-Tcf/Lef transcriptional activity by beta-catenin, showing that it requires direct interaction between beta-catenin and beta-catenin. We further showed that it involves recruitment of Gli3R, the short transcription-repressing form of the transcription factor Gli3, to beta-catenin by beta-catenin. The resulting inhibition of beta-catenin transcriptional activity leads to increased expression of type II collagen. Gli3R and beta-catenin actions are co-dependent: both are necessary for the observed inhibitory effects on beta-catenin transcriptional activity. Reducing Gli3R expression levels through activation of Indian Hedgehog (Ihh) signaling also is sufficient to activate beta-catenin transcriptional activity, suggesting that the ternary complex, Gli3R.beta-catenin.beta-catenin, mediates Ihh-dependent activation of Wnt/beta-catenin signaling in articular chondrocytes. Collectively, this study shows that beta-catenin functions as a nuclear factor that recruits the transcriptional repressor Gli3R to beta-catenin to inhibit beta-catenin transcriptional activity and dedifferentiation of articular chondrocytes. Finally, osteoarthritic cartilage showed elevated levels of beta-catenin and decreased levels of beta-catenin and Gli3R, suggesting that decreased levels of -catenin and Gli3R levels contribute to increased beta-catenin transcriptional activity during osteoarthritic cartilage destruction. |
|
