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The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis

Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors anta...

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Autores principales: Miyauchi, Yoshiteru, Ninomiya, Ken, Miyamoto, Hiroya, Sakamoto, Akemi, Iwasaki, Ryotaro, Hoshi, Hiroko, Miyamoto, Kana, Hao, Wu, Yoshida, Shigeyuki, Morioka, Hideo, Chiba, Kazuhiro, Kato, Shigeaki, Tokuhisa, Takeshi, Saitou, Mitinori, Toyama, Yoshiaki, Suda, Toshio, Miyamoto, Takeshi
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856022/
https://www.ncbi.nlm.nih.gov/pubmed/20368579
http://dx.doi.org/10.1084/jem.20091957
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author Miyauchi, Yoshiteru
Ninomiya, Ken
Miyamoto, Hiroya
Sakamoto, Akemi
Iwasaki, Ryotaro
Hoshi, Hiroko
Miyamoto, Kana
Hao, Wu
Yoshida, Shigeyuki
Morioka, Hideo
Chiba, Kazuhiro
Kato, Shigeaki
Tokuhisa, Takeshi
Saitou, Mitinori
Toyama, Yoshiaki
Suda, Toshio
Miyamoto, Takeshi
author_facet Miyauchi, Yoshiteru
Ninomiya, Ken
Miyamoto, Hiroya
Sakamoto, Akemi
Iwasaki, Ryotaro
Hoshi, Hiroko
Miyamoto, Kana
Hao, Wu
Yoshida, Shigeyuki
Morioka, Hideo
Chiba, Kazuhiro
Kato, Shigeaki
Tokuhisa, Takeshi
Saitou, Mitinori
Toyama, Yoshiaki
Suda, Toshio
Miyamoto, Takeshi
author_sort Miyauchi, Yoshiteru
collection PubMed
description Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte–induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets ‘osteoclastic’ molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1–Bcl6–osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.
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spelling pubmed-28560222010-10-12 The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis Miyauchi, Yoshiteru Ninomiya, Ken Miyamoto, Hiroya Sakamoto, Akemi Iwasaki, Ryotaro Hoshi, Hiroko Miyamoto, Kana Hao, Wu Yoshida, Shigeyuki Morioka, Hideo Chiba, Kazuhiro Kato, Shigeaki Tokuhisa, Takeshi Saitou, Mitinori Toyama, Yoshiaki Suda, Toshio Miyamoto, Takeshi J Exp Med Article Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte–induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets ‘osteoclastic’ molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1–Bcl6–osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies. The Rockefeller University Press 2010-04-12 /pmc/articles/PMC2856022/ /pubmed/20368579 http://dx.doi.org/10.1084/jem.20091957 Text en © 2010 Miyauchi et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Miyauchi, Yoshiteru
Ninomiya, Ken
Miyamoto, Hiroya
Sakamoto, Akemi
Iwasaki, Ryotaro
Hoshi, Hiroko
Miyamoto, Kana
Hao, Wu
Yoshida, Shigeyuki
Morioka, Hideo
Chiba, Kazuhiro
Kato, Shigeaki
Tokuhisa, Takeshi
Saitou, Mitinori
Toyama, Yoshiaki
Suda, Toshio
Miyamoto, Takeshi
The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
title The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
title_full The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
title_fullStr The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
title_full_unstemmed The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
title_short The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
title_sort blimp1–bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856022/
https://www.ncbi.nlm.nih.gov/pubmed/20368579
http://dx.doi.org/10.1084/jem.20091957
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