Hwang Sang-Gu, Yu Sung-Sook, Lee Soo-Woong, Chun Jang-Soo
Department of Life Science, Gwangju Institute of Science and Technology, Buk-Gu, Gwangju 500-712, Korea.
FEBS Lett. 2005 Aug 29;579(21):4837-42. doi: 10.1016/j.febslet.2005.07.067.
Our previous study indicated that interleukin (IL)-1beta 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 beta-catenin transcriptional activity. Wnt-3a also induced dedifferentiation of articular chondrocytes by stimulating the transcriptional activity of beta-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 beta-catenin-Tcf/Lef transcriptional complex and the c-Jun/AP-1 pathway.
我们之前的研究表明，白细胞介素（IL）-1β可诱导软骨细胞中多种Wnt蛋白的表达，并通过c-Jun/激活蛋白-1（AP-1）途径导致软骨细胞去分化。本研究检测了Wnt-3a是否通过c-Jun/AP-1途径导致软骨细胞去分化。Wnt-3a通过稳定细胞间黏附来抑制间充质细胞的软骨形成，其方式独立于β-连环蛋白的转录活性。Wnt-3a还通过刺激β-连环蛋白-T细胞因子/淋巴增强因子（Tcf/Lef）复合物的转录活性来诱导关节软骨细胞去分化。在软骨细胞中，Wnt-3a导致c-Jun的表达及其被c-Jun氨基末端激酶（JNK）磷酸化，从而导致AP-1激活。AP-1激活抑制了Sox-9的表达，Sox-9是调节II型胶原表达的主要转录因子。总体而言，我们的结果表明，Wnt-3a通过稳定细胞间黏附来抑制软骨形成，并且它通过激活β-连环蛋白-Tcf/Lef转录复合物和c-Jun/AP-1途径导致软骨细胞去分化。
