Activating -catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

作者：Jie, Zhiwei; Shen, Shuying; Zhao, Xiangde; Xu, Wenbin; Zhang, Xuyang; Huang, Bao; Tang, Pan; Qin, An; Fan, Shunwu^*; Xie, Ziang^*

来源：The FASEB Journal, 2019, 33(3): 4236-4247.

DOI：10.1096/fj.201801977R

• bone loss
• osteoclast
• VX-745
• SKL2001
• therapeutic

Balance of osteoclast formation is regulated by the receptor activator of NF-B ligand and extracellular negative regulators such as IFN- and IFN-. However, very little is known about the intrinsic negative regulatory factors of osteoclast differentiation. Recently, the paired-box homeodomain transcription factor Pax6 was shown to negatively regulate receptor activator of NF-B ligand-mediated osteoclast differentiation. However, the mechanism underlying this regulation is still unclear. In this study, we show that a p38 inhibitor (VX-745) up-regulates the expression of Pax6 during osteoclast differentiation. Subsequently, we found that -catenin could bind to the proximal region of Pax6 promoter to induce its expression, and this action could be impaired by p38-induced ubiquitin-mediated degradation of -catenin. Our results suggest that Pax6 is regulated by a novel p38/-catenin pathway. Pax6 can further regulate the nuclear translocation of NF of activated T cells, cytoplasmic 1. Our study indicates that this novel p38/-catenin/Pax6 axis contributes to negative regulation of osteoclastogenesis. In addition, our study proposes a novel approach to treat osteoclast-related diseases through the use of VX-745 complemented with the -catenin activator SKL2001.Jie, Z., Shen, S., Zhao, X., Xu, W., Zhang, X., Huang, B., Tang, P., Qin, A., Fan, S., Xie, Z. Activating -catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK.

• 出版日期2019-3
• 单位上海交通大学; 浙江大学