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Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation

Osteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast dif...

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Autores principales: Baba, Masaya, Endoh, Mitsuhiro, Ma, Wenjuan, Toyama, Hirofumi, Hirayama, Akiyoshi, Nishikawa, Keizo, Takubo, Keiyo, Hano, Hiroyuki, Hasumi, Hisashi, Umemoto, Terumasa, Hashimoto, Michihiro, Irie, Nobuko, Esumi, Chiharu, Kataoka, Miho, Nakagata, Naomi, Soga, Tomoyoshi, Yao, Masahiro, Kamba, Tomomi, Minami, Takashi, Ishii, Masaru, Suda, Toshio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220829/
https://www.ncbi.nlm.nih.gov/pubmed/29893999
http://dx.doi.org/10.1002/jbmr.3477
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author Baba, Masaya
Endoh, Mitsuhiro
Ma, Wenjuan
Toyama, Hirofumi
Hirayama, Akiyoshi
Nishikawa, Keizo
Takubo, Keiyo
Hano, Hiroyuki
Hasumi, Hisashi
Umemoto, Terumasa
Hashimoto, Michihiro
Irie, Nobuko
Esumi, Chiharu
Kataoka, Miho
Nakagata, Naomi
Soga, Tomoyoshi
Yao, Masahiro
Kamba, Tomomi
Minami, Takashi
Ishii, Masaru
Suda, Toshio
author_facet Baba, Masaya
Endoh, Mitsuhiro
Ma, Wenjuan
Toyama, Hirofumi
Hirayama, Akiyoshi
Nishikawa, Keizo
Takubo, Keiyo
Hano, Hiroyuki
Hasumi, Hisashi
Umemoto, Terumasa
Hashimoto, Michihiro
Irie, Nobuko
Esumi, Chiharu
Kataoka, Miho
Nakagata, Naomi
Soga, Tomoyoshi
Yao, Masahiro
Kamba, Tomomi
Minami, Takashi
Ishii, Masaru
Suda, Toshio
author_sort Baba, Masaya
collection PubMed
description Osteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast differentiation. However, the upstream regulatory mechanisms that drive these metabolic changes in osteoclastogenesis remain to be elucidated. Here, we demonstrate that induced deletion of a tumor suppressor gene, Folliculin (Flcn), in mouse osteoclast precursors causes severe osteoporosis in 3 weeks through excess osteoclastogenesis. Flcn‐deficient osteoclast precursors reveal cell autonomous accelerated osteoclastogenesis with increased sensitivity to receptor activator of NF‐κB ligand (RANKL). We demonstrate that Flcn regulates oxidative phosphorylation and purine metabolism through suppression of nuclear localization of the transcription factor Tfe3, thereby inhibiting expression of its target gene Pgc1. Metabolome studies revealed that Flcn‐deficient osteoclast precursors exhibit significant augmentation of oxidative phosphorylation and nucleotide production, resulting in an enhanced purinergic signaling loop that is composed of controlled ATP release and autocrine/paracrine purinergic receptor stimulation. Inhibition of this purinergic signaling loop efficiently blocks accelerated osteoclastogenesis in Flcn‐deficient osteoclast precursors. Here, we demonstrate an essential and novel role of the Flcn‐Tfe3‐Pgc1 axis in osteoclastogenesis through the metabolic reprogramming of oxidative phosphorylation and purine metabolism. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
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spelling pubmed-62208292018-11-13 Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation Baba, Masaya Endoh, Mitsuhiro Ma, Wenjuan Toyama, Hirofumi Hirayama, Akiyoshi Nishikawa, Keizo Takubo, Keiyo Hano, Hiroyuki Hasumi, Hisashi Umemoto, Terumasa Hashimoto, Michihiro Irie, Nobuko Esumi, Chiharu Kataoka, Miho Nakagata, Naomi Soga, Tomoyoshi Yao, Masahiro Kamba, Tomomi Minami, Takashi Ishii, Masaru Suda, Toshio J Bone Miner Res Original Articles Osteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast differentiation. However, the upstream regulatory mechanisms that drive these metabolic changes in osteoclastogenesis remain to be elucidated. Here, we demonstrate that induced deletion of a tumor suppressor gene, Folliculin (Flcn), in mouse osteoclast precursors causes severe osteoporosis in 3 weeks through excess osteoclastogenesis. Flcn‐deficient osteoclast precursors reveal cell autonomous accelerated osteoclastogenesis with increased sensitivity to receptor activator of NF‐κB ligand (RANKL). We demonstrate that Flcn regulates oxidative phosphorylation and purine metabolism through suppression of nuclear localization of the transcription factor Tfe3, thereby inhibiting expression of its target gene Pgc1. Metabolome studies revealed that Flcn‐deficient osteoclast precursors exhibit significant augmentation of oxidative phosphorylation and nucleotide production, resulting in an enhanced purinergic signaling loop that is composed of controlled ATP release and autocrine/paracrine purinergic receptor stimulation. Inhibition of this purinergic signaling loop efficiently blocks accelerated osteoclastogenesis in Flcn‐deficient osteoclast precursors. Here, we demonstrate an essential and novel role of the Flcn‐Tfe3‐Pgc1 axis in osteoclastogenesis through the metabolic reprogramming of oxidative phosphorylation and purine metabolism. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR). John Wiley and Sons Inc. 2018-06-26 2018-10 /pmc/articles/PMC6220829/ /pubmed/29893999 http://dx.doi.org/10.1002/jbmr.3477 Text en © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR) This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Baba, Masaya
Endoh, Mitsuhiro
Ma, Wenjuan
Toyama, Hirofumi
Hirayama, Akiyoshi
Nishikawa, Keizo
Takubo, Keiyo
Hano, Hiroyuki
Hasumi, Hisashi
Umemoto, Terumasa
Hashimoto, Michihiro
Irie, Nobuko
Esumi, Chiharu
Kataoka, Miho
Nakagata, Naomi
Soga, Tomoyoshi
Yao, Masahiro
Kamba, Tomomi
Minami, Takashi
Ishii, Masaru
Suda, Toshio
Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation
title Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation
title_full Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation
title_fullStr Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation
title_full_unstemmed Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation
title_short Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation
title_sort folliculin regulates osteoclastogenesis through metabolic regulation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220829/
https://www.ncbi.nlm.nih.gov/pubmed/29893999
http://dx.doi.org/10.1002/jbmr.3477
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