Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation

• Published in: Nature communications 2014-11, Vol.5 (1), p.5418-5418, Article 5418
• Main Authors: Park-Min, Kyung-Hyun, Lim, Elisha, Lee, Min Joon, Park, Sung Ho, Giannopoulou, Eugenia, Yarilina, Anna, van der Meulen, Marjolein, Zhao, Baohong, Smithers, Nicholas, Witherington, Jason, Lee, Kevin, Tak, Paul P., Prinjha, Rab K., Ivashkiv, Lionel B
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/89; 631/250/249/2510; 631/337/176; 64/60; 692/698/690/797; 96/95; Animals; Arthritis; Bone Resorption - physiopathology; Cell Differentiation - physiology; Cells, Cultured; Epigenesis, Genetic - physiology; Epigenetics; Female; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humanities and Social Sciences; Humans; Inflammation - physiopathology; Mice; Mice, Inbred C57BL; multidisciplinary; NFATC Transcription Factors - antagonists & inhibitors; NFATC Transcription Factors - physiology; Oophorectomy; Osteoclasts - drug effects; Osteoclasts - physiology; Osteogenesis - drug effects; Osteogenesis - physiology; Osteoporosis; Osteoporosis - physiopathology; Ovariectomy; Proteins; RANK Ligand - physiology; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6418

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. Epigenetic changes during the differentiation of bone-resorbing cells have important implications in bone remodelling. Here the authors target this pathway with I-BET151, an inhibitor of bromo and extra-terminal proteins that inhibits expression of the MYC-NFAT axis and suppresses bone loss in multiple mouse models.