title: The IRE1α-XBP1 pathway positively regulates parathyroid hormone (PTH)/PTH-related peptide receptor expression and is involved in pth-induced osteoclastogenesis.
abstract: To address the "endoplasmic reticulum stress" triggered by the burden of protein synthesis, the unfolded protein response is induced during osteoblast differentiation. In this study, we show that the transcription of parathyroid hormone (PTH)/PTH-related peptide receptor (PTH1R) is regulated by one of the endoplasmic reticulum-stress mediators, the IRE1α-XBP1 pathway, in osteoblasts. We found that the increase in Pth1r transcription upon BMP2 treatment is significantly suppressed in mouse embryonic fibroblasts lacking IRE1α. As expected, gene silencing of Ire1α and Xbp1 resulted in a decrease in Pth1r transcripts in BMP2-treated embryonic fibroblasts. We identified two potential binding sites for XBP1 in the promoter region of Pth1r and found that XBP1 promotes the transcription of Pth1r by directly binding to those sites. Moreover, we confirmed that the gene silencing of Xbp1 suppresses PTH-induced Rankl expression in primary osteoblasts and thereby abolishes osteoclast formation in an in vitro model of osteoclastogenesis. Thus, the present study reveals potential involvement of the IRE1α-XBP1 pathway in PTH-induced osteoclastogenesis through the regulation of PTH1R expression.
authors.affiliation: Department of Anti-aging Orthopedic Research, Keio University, School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Tohmonda
authors.forename: Masaki
authors.initials: M
authors.lastname: Yoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuochi
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
mesh_terms: D000818:Animals; D001665:Binding Sites; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D004622:Embryo, Mammalian; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics* / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D004268:DNA-Binding Proteins; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D044168:Receptor, Parathyroid Hormone, Type 1; D000071701:Regulatory Factor X Transcription Factors; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases