Please use this identifier to cite or link to this item: https://doi.org/10.1002/jbmr.3477
Title: Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation
Authors: Baba, M
Endoh, M 
Ma, W
Toyama, H
Hirayama, A
Nishikawa, K
Takubo, K
Hano, H
Hasumi, H
Umemoto, T
Hashimoto, M
Irie, N
Esumi, C
Kataoka, M
Nakagata, N
Soga, T
Yao, M
Kamba, T
Minami, T
Ishii, M
Suda, T 
Keywords: estrone
osteoclast differentiation factor
purinergic receptor
transcription factor
transcription factor Tfe3
unclassified drug
basic helix loop helix leucine zipper transcription factor
Bhd protein, mouse
oncoprotein
peroxisome-proliferator-activated receptor-gamma coactivator-1
purine derivative
Tcfe3 protein, mouse
transcription factor
tumor suppressor protein
animal cell
animal cell culture
animal experiment
animal model
Article
DNA microarray
flow cytometry
immunocytochemistry
in vitro study
metabolic regulation
mitochondrial biogenesis
mouse
nonhuman
osteoclastogenesis
osteoporosis
oxidative phosphorylation
purine metabolism
RAW 264.7 cell line
tumor suppressor gene
animal
bone development
bone marrow
knockout mouse
metabolism
organelle biogenesis
osteoclast
osteoporosis
pathology
signal transduction
upregulation
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Bone Marrow
Mice
Mice, Knockout
Organelle Biogenesis
Osteoclasts
Osteogenesis
Osteoporosis
Oxidative Phosphorylation
Proto-Oncogene Proteins
Purines
RAW 264.7 Cells
Signal Transduction
Transcription Factors
Tumor Suppressor Proteins
Up-Regulation
Issue Date: 2018
Publisher: John Wiley and Sons Inc.
Citation: Baba, M, Endoh, M, Ma, W, Toyama, H, Hirayama, A, Nishikawa, K, Takubo, K, Hano, H, Hasumi, H, Umemoto, T, Hashimoto, M, Irie, N, Esumi, C, Kataoka, M, Nakagata, N, Soga, T, Yao, M, Kamba, T, Minami, T, Ishii, M, Suda, T (2018). Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation. Journal of Bone and Mineral Research 33 (10) : 1785-1798. ScholarBank@NUS Repository. https://doi.org/10.1002/jbmr.3477
Abstract: 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-?B 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). © 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)
Source Title: Journal of Bone and Mineral Research
URI: https://scholarbank.nus.edu.sg/handle/10635/175103
ISSN: 0884-0431
DOI: 10.1002/jbmr.3477
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