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ARS Home » Plains Area » College Station, Texas (RAFSRU) » Responsive Agricultural Food Systems Research Unit » Research » Publications at this Location » Publication #426656
Research Project: Human Nutrition through Food Systems

Location: Responsive Agricultural Food Systems Research Unit

Title: IRE1 signaling in osteoprogenitors augments beta-catenin activity and physiologic bone accrual

Author
item LAKSHMI, KOLORA - University Of Colorado
item MELENDEZ-SUCHI, CHRISTIAN - University Of Arkansas
item BUTLER, VERONICA - University Of Colorado
item HAN, LI - University Of Arkansas
item ALMEIDA, MARIA - University Of Arkansas
item Shankar, Kartik
item ADAMS, DOUGLAS - University Of Colorado
item IYER, SRIVIDHYA - Texas A&M University

Submitted to: Journal of Bone and Mineral Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/27/2025
Publication Date: 1/6/2026
Citation: Lakshmi, K., Melendez-Suchi, C., Butler, V., Han, L., Almeida, M., Shankar, K., Adams, D., Iyer, S. 2026. IRE1 signaling in osteoprogenitors augments beta-catenin activity and physiologic bone accrual. Journal of Bone and Mineral Research. 41(8):890-902. https://doi.org/10.1093/jbmr/zjag001.
DOI: https://doi.org/10.1093/jbmr/zjag001

Interpretive Summary: Bone formation by osteoblasts involves the synthesis, folding and modification of a multitude of membrane and secretory proteins. The Unfolded Protein Response (UPR) fine tunes the protein folding capacity of the endoplasmic reticulum (ER) in eukaryotic cells via the actions of PERK, IRE1 and ATF6 proteins. However, the specific contributions of these proteins to bone health have not been investigated. These studies investigated the roles of key sensors of the unfolded protein response in osteoblasts using cell-type specific deletion of these regulators and via in vitro studies. The studies demonstrate that abolishing PERK and ATF6 activity in the osteoblast lineage has no effect on bone mass or strength. However, deletion of IRE1 reveals a novel regulatory role in stimulating osteoprogenitor proliferation by stimulating ß-catenin/TCF mediated transcription and subsequent bone formation.

Technical Abstract: 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 (i.e. Ire1a, Perk, or Atf6) in the osteoblast lineage using the Osx1-Cre transgene were determined. Mice with deletion of Ire1' in Osx1+ osteoblast precursors exhibited a marked reduction in osteoblast number, bone mass, and strength. Primary bone marrow cultures of osteoprogenitors lacking Ire1' had significantly reduced proliferation, alkaline phosphatase activity, and survival. Analyses of bulk RNA-seq data revealed suppression of osteogenic signature by Ire1a deletion in Osx1+ cells and predicted suppression of ß-catenin activity. Mechanistically, Ire1a augments nuclear translocation and transcriptional activity of b-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 b-catenin activity in osteoprogenitors.