Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK. Issue 3 (7th December 2018)

• Record Type: Journal Article
• Authors: Jie, Zhiwei; Shen, Shuying; Zhao, Xiangde; Xu, Wenbin; Zhang, Xuyang; Huang, Bao; Tang, Pan; Qin, An; Fan, Shunwu; Xie, Ziang
• Is Part Of: FASEB journal. Volume 33:Issue 3(2019)
• Page Start: 4236
• Page End: 4247
• Publication Date: 2018-12-07
• Subjects: bone loss -- osteoclast -- VX-745 -- SKL2001 -- therapeutic; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201801977R
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: Balance of osteoclast formation is regulated by the receptor activator of NF‐κB ligand and extracellular negative regulators such as IFN‐γ and IFN‐β. 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‐κB 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 β‐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 β‐catenin. Our results suggest that Pax6 is regulated by a novel p38/β‐catenin pathway. Pax6 can further regulate the nuclear translocation of NF of activated T cells, cytoplasmic 1. Our study indicates that this novel p38/β‐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 β‐catenin activator SKL2001.—Jie, Z., Shen, S., Zhao, X., Xu, W., Zhang, X., Huang B., Tang P., Qin, A., Fan, S., Xie, Z. Activating β‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK. FASEB J. 33, 4236–4247 (2019). www.fasebj.org