Emerging evidence suggests that ​RANKL-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 ​I-BET151 that targets bromo and extra-terminal (BET) proteins that ‘read’ chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. ​I-BET151 suppresses pathologic bone loss in ​TNF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a ​MYC-NFAT axis important for osteoclastogenesis. Mechanistically, ​I-BET151 inhibits expression of the master osteoclast regulator ​NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator ​MYC. ​MYC is elevated in rheumatoid arthritis macrophages and its induction by ​RANKL is important for osteoclastogenesis and ​TNF-induced bone resorption. These findings highlight the importance of an ​I-BET151-inhibited ​MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption…

Originally posted on Nature Communications

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