IRE1 signaling in osteoprogenitors augments β-catenin activity and physiologic bone accrual

The endoplasmic reticulum (ER) orchestrates the folding of the large amounts of membrane and secretory proteins that are synthesized during the process of osteogenesis. The unfolded protein response (UPR) resulting from accumulation of misfolded proteins in the ER lumen either promotes or inhibits osteoblast differentiation in vitro depending on magnitude and duration. All three transducers of the UPR, namely, IRE, PERK, and ATF6 proteins, have been implicated in skeletal biology, yet their specific contribution to osteoblast differentiation and function in vivo has not been investigated systematically. Here, the skeletal consequences of deleting each of them (ie, Ire1α, Perk, or Atf6) in the osteoblast lineage using the Osx1-Cre transgene were determined. Mice with deletion of Ire1α in Osx1+ osteoblast precursors exhibited a marked reduction in osteoblast number, bone mass, and strength. Primary bone marrow cultures of osteoprogenitors lacking Ire1α had significantly reduced proliferation, alkaline phosphatase activity, and survival. Analyses of bulk RNA-seq data revealed suppression of osteogenic signature by Ire1α deletion in Osx1+ cells and predicted suppression of β-catenin activity. Mechanistically, Ire1α augments nuclear translocation and transcriptional activity of β-catenin in Osx1+ cells. In contrast, deletion of Perk or Atf6 genes in the osteoblast lineage using the Osx1-Cre transgene did not alter bone mass or strength. Collectively, these studies demonstrate that IRE1, but not other UPR transducers, promote physiological bone accrual in part by boosting β-catenin activity in osteoprogenitors.