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

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 () and Lionel B Ivashkiv ()
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Kyung-Hyun Park-Min: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery
Elisha Lim: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery
Min Joon Lee: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery
Sung Ho Park: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery
Eugenia Giannopoulou: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery
Anna Yarilina: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery
Marjolein van der Meulen: Sibley School of Mechanical and Aerospace Engineering, Cornell University
Baohong Zhao: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery
Nicholas Smithers: Epinova DPU, GlaxoSmithKline, Medicines Research Centre
Jason Witherington: Epinova DPU, GlaxoSmithKline, Medicines Research Centre
Kevin Lee: Epinova DPU, GlaxoSmithKline, Medicines Research Centre
Paul P. Tak: Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre
Rab K. Prinjha: Epinova DPU, GlaxoSmithKline, Medicines Research Centre
Lionel B Ivashkiv: Arthritis and Tissue Degeneration Program and David C. Rosensweig Center for Genomics Research, Hospital for Special Surgery

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms6418

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