Authors
Kyung-Hyun Park-Min, Elisha Lim, Min Joon Lee, Sung Ho Park, Eugenia Giannopoulou, Anna Yarilina, Marjolein van der Meulen, Baohong Zhao, Nicholas Smithers, Jason Witherington, Kevin Lee, Paul P. Tak, Rab K. Prinjha & Lionel B Ivashkiv
Abstract
Emerging evidence suggests that ANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study, we find that the small molecule -BET151 that targets bromo and extra-terminal (BET) proteins that ‘read’ chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. -BET151 suppresses pathologic bone loss in NF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a YC-NFAT axis important for osteoclastogenesis. Mechanistically, -BET151 inhibits expression of the master osteoclast regulator FATC1 by suppressing expression and recruitment of its newly identified upstream regulator YC. YC is elevated in rheumatoid arthritis macrophages and its induction by ANKL is important for osteoclastogenesis and NF-induced bone resorption. These findings highlight the importance of an -BET151-inhibited YC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption.