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박성호

Park, Sung Ho
Laboratory of Molecular Immunology
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Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation

Author(s)
Park-Min, Kyung-HyunLim, ElishaLee, Min JoonPark, Sung HoGiannopoulou, EugeniaYarilina, Annavan der Meulen, MarjoleinZhao, BaohongSmithers, NicholasWitherington, JasonLee, KevinTak, Paul P.Prinjha, Rab K.Ivashkiv, Lionel B.
Issued Date
2014-11
DOI
10.1038/ncomms6418
URI
https://scholarworks.unist.ac.kr/handle/201301/26375
Fulltext
https://www.nature.com/articles/ncomms6418
Citation
NATURE COMMUNICATIONS, v.5, pp.5418
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.
Publisher
NATURE PUBLISHING GROUP
ISSN
2041-1723
Keyword
ACUTE MYELOID-LEUKEMIARHEUMATOID-ARTHRITISC-MYCBROMODOMAIN INHIBITIONSELECTIVE-INHIBITIONNEGATIVE REGULATIONDIFFERENTIATIONNFATC1CANCEROSTEOIMMUNOLOGY

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