Wnt-3a regulates chondrocyte differentiation via c-Jun/AP-1 pathway

Our previous study indicated that interleukin (IL)-1β induces expression of several Wnt proteins in chondrocytes and causes chondrocyte dedifferentiation via the c-Jun/activator protein-1 (AP-1) pathway. This study examined whether Wnt-3a causes chondrocyte dedifferentiation via the c-Jun/AP-1 pathway. Wnt-3a inhibited chondrogenesis of mesenchymal cells by stabilizing cell–cell adhesion in a manner independent of β-catenin transcriptional activity. Wnt-3a also induced dedifferentiation of articular chondrocytes by stimulating the transcriptional activity of β-catenin-T cell-factor/lymphoid-enhancer-factor (Tcf/Lef) complex. In chondrocytes, Wnt-3a caused the expression of c-Jun and its phosphorylation by c-Jun N-terminal kinase (JNK), resulting in activation of AP-1. AP-1 activation suppressed the expression of Sox-9, a major transcription factor regulating type II collagen expression. Collectively, our results suggest that Wnt-3a inhibits chondrogenesis by stabilizing cell–cell adhesion and that it causes dedifferentiation of chondrocytes by activating of β-catenin-Tcf/Lef transcriptional complex and the c-Jun/AP-1 pathway.