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Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation

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-termi...

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Autores principales: Park-Min, Kyung-Hyun, Lim, Elisha, Lee, Min Joon, Park, Sung Ho, Giannopoulos, Eugenia, Yarilina, Anna, van der Meulen, Marjolein, Zhao, Baohong, Smithers, Nicholas, Witherington, Jason, Lee, Kevin, Tak, Paul P., Prinjha, Rab K., Ivashkiv, Lionel B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249944/
https://www.ncbi.nlm.nih.gov/pubmed/25391636
http://dx.doi.org/10.1038/ncomms6418
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author Park-Min, Kyung-Hyun
Lim, Elisha
Lee, Min Joon
Park, Sung Ho
Giannopoulos, Eugenia
Yarilina, Anna
van der Meulen, Marjolein
Zhao, Baohong
Smithers, Nicholas
Witherington, Jason
Lee, Kevin
Tak, Paul P.
Prinjha, Rab K.
Ivashkiv, Lionel B.
author_facet Park-Min, Kyung-Hyun
Lim, Elisha
Lee, Min Joon
Park, Sung Ho
Giannopoulos, Eugenia
Yarilina, Anna
van der Meulen, Marjolein
Zhao, Baohong
Smithers, Nicholas
Witherington, Jason
Lee, Kevin
Tak, Paul P.
Prinjha, Rab K.
Ivashkiv, Lionel B.
author_sort Park-Min, Kyung-Hyun
collection PubMed
description 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 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 estrogen deficiency-mediated pathologic bone resorption.
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spelling pubmed-42499442015-05-13 Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation Park-Min, Kyung-Hyun Lim, Elisha Lee, Min Joon Park, Sung Ho Giannopoulos, Eugenia Yarilina, Anna van der Meulen, Marjolein Zhao, Baohong Smithers, Nicholas Witherington, Jason Lee, Kevin Tak, Paul P. Prinjha, Rab K. Ivashkiv, Lionel B. Nat Commun Article 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 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 estrogen deficiency-mediated pathologic bone resorption. 2014-11-13 /pmc/articles/PMC4249944/ /pubmed/25391636 http://dx.doi.org/10.1038/ncomms6418 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Park-Min, Kyung-Hyun
Lim, Elisha
Lee, Min Joon
Park, Sung Ho
Giannopoulos, Eugenia
Yarilina, Anna
van der Meulen, Marjolein
Zhao, Baohong
Smithers, Nicholas
Witherington, Jason
Lee, Kevin
Tak, Paul P.
Prinjha, Rab K.
Ivashkiv, Lionel B.
Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation
title Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation
title_full Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation
title_fullStr Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation
title_full_unstemmed Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation
title_short Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation
title_sort inhibition of osteoclastogenesis and inflammatory bone resorption by targeting bet proteins and epigenetic regulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249944/
https://www.ncbi.nlm.nih.gov/pubmed/25391636
http://dx.doi.org/10.1038/ncomms6418
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