The endoplasmic reticulum proteostasis network and bone disease.

Bone homeostasis relies on the coordinated activity of osteoblasts and osteoclasts that balances bone formation and resorption, and of osteocytes for biomechanical sensing and hormone secretion. A key factor in the function of these cells is proteostasis, where the endoplasmic reticulum (ER) oversees protein synthesis, quality control, folding, and the secretion of proteins such as collagen type I. Emerging research links ER proteostasis defects to skeletal disorders caused by impaired bone development and mass. We explore the mechanisms of ER proteostasis, including the unfolded protein response (UPR), and discuss how genetic, metabolic, and environmental factors disrupt these pathways and contribute to bone pathology. We also highlight the need for further mechanistic insights which could pave the way for novel therapies that target ER-Golgi traffic and inhibit ER stress in bone diseases.