Stage-dependent endoplasmic reticulum homeostasis in osteogenic differentiation.

Osteoporosis (OP) is primarily characterized by reduced bone mass, microarchitectural deterioration, and an increased susceptibility to fragility fractures. A central pathological feature of OP is the progressive impairment of osteogenic differentiation and bone matrix production in osteoblasts. The endoplasmic reticulum (ER), a pivotal organelle responsible for secretory protein folding, lipid/sterol biosynthesis, and intracellular Ca2+ storage, is subjected to a substantial secretory burden during osteogenic differentiation and functions as a critical regulatory hub integrating metabolic stress, inflammatory signaling, and mineralization-associated calcium signaling. Emerging evidence indicates that disruption of ER homeostasis regulates osteogenic differentiation through the three canonical branches of the unfolded protein response (UPR), including PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 signaling pathways. In parallel, selective ER autophagy (ER-phagy) dynamically regulates ER quality control during osteogenic differentiation through removal of damaged ER domains and misfolded substrates such as procollagen. In addition, ER Ca2+ stores and STIM/ORAI-mediated store-operated Ca2+ entry (SOCE) cooperatively maintain calcium homeostasis during osteogenesis and regulate spatiotemporal expression of osteogenic transcription factors, including Runx2 and Sp7, through Ca2+ oscillatory signaling. ER membrane lipid composition further modulate osteogenic fate by influencing membrane contact site dynamics and cellular metabolic adaptation. In this review, we systematically summarize the crosstalk among ER stress, ER-phagy, Ca2+ homeostasis, and lipid metabolism during osteogenic differentiation from the perspective of ER structure-function coupling. We further discuss potential therapeutic strategies targeting ER stress regulation, including chemical chaperones and UPR/autophagy modulators, to provide new insights for targeted therapeutic approaches for osteoporosis.