RRC ID 37950
Author Tohmonda T, Yoda M, Iwawaki T, Matsumoto M, Nakamura M, Mikoshiba K, Toyama Y, Horiuchi K.
Title IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis.
Journal J Clin Invest
Abstract The unfolded protein response (UPR) is a cellular adaptive mechanism that is activated in response to the accumulation of unfolded proteins in the endoplasmic reticulum. The inositol-requiring protein-1α/X-box-binding protein-mediated (IRE1α/XBP1-mediated) branch of the UPR is highly conserved and has also been shown to regulate various cell-fate decisions. Herein, we have demonstrated a crucial role for the IREα/XBP1-mediated arm of the UPR in osteoclast differentiation. Using murine models, we found that the conditional abrogation of IRE1α in bone marrow cells increases bone mass as the result of defective osteoclastic bone resorption. In osteoclast precursors, IRE1α was transiently activated during osteoclastogenesis, and suppression of the IRE1α/XBP1 pathway in these cells substantially inhibited the formation of multinucleated osteoclasts in vitro. We determined that XBP1 directly binds the promoter and induces transcription of the gene encoding the master regulator of osteoclastogenesis nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, activation of IRE1α was partially dependent on Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate receptors 2 and 3 (ITPR2 and ITPR3) in the endoplasmic reticulum, as pharmacological inhibition or deletion of these receptors markedly decreased Xbp1 mRNA processing. The present study thus reveals an intracellular pathway that integrates the UPR and osteoclast differentiation through activation of the IRE1α/XBP1 pathway.
Volume 125(8)
Pages 3269-79
Published 2015-8-3
DOI 10.1172/JCI76765
PII 76765
PMID 26193638
PMC PMC4563737
MeSH Animals Bone Marrow Cells / cytology Bone Marrow Cells / metabolism* Calcium Signaling / physiology Cell Differentiation / physiology* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Endoribonucleases / genetics Endoribonucleases / metabolism* Inositol 1,4,5-Trisphosphate Receptors / genetics Inositol 1,4,5-Trisphosphate Receptors / metabolism Mice Mice, Knockout NFATC Transcription Factors / genetics NFATC Transcription Factors / metabolism Osteoclasts / cytology Osteoclasts / metabolism* Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* Regulatory Factor X Transcription Factors Transcription Factors / genetics Transcription Factors / metabolism* Unfolded Protein Response / physiology* X-Box Binding Protein 1
IF 11.864
Times Cited 16
Human and Animal Cells RAW 264(RCB0535) 293T(RCB2202) 293gp(RCB2354)