The IRE1α-XBP1 pathway positively regulates parathyroid hormone (PTH)/PTH-related peptide receptor expression and is involved in PTH-induced osteoclastogenesis

Background: XBP1 is a transcription factor that is activated by one of the ER stress sensors, IRE1. Results: XBP1 promotes the expression of PTH/PTH-related peptide receptor in osteoblasts and renders these cells responsive to PTH. Conclusion: The IRE1-XBP1 pathway indirectly regulates PTH-induced osteoclastogenesis. Significance: This study may be the first to reveal the potential link between ER stress sensors and the regulation of osteoclastogenesis. 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 IRE1-XBP1 pathway in PTH-induced osteoclastogenesis through the regulation of PTH1R expression.