ED-71 prevents glucocorticoid-induced bone loss by inhibiting type H vascular endothelial cell senescence through maintaining mitochondria-associated membrane-mediated calcium homeostasis.

Glucocorticoids (GCs) are widely used in anti-inflammatory and immunosuppressive therapies. However, long-term or high-dose administration of GCs often leads to bone loss, resulting in GC-induced osteoporosis (GIOP). GIOP reduces bone strength, increases fracture risk, and affects the quality of life and treatment compliance of patients. Therefore, there is an urgent need to develop new therapeutic drugs for GIOP. This study found that the active vitamin D analog eldecalcitol (ED-71) can prevent GIOP by inhibiting vascular endothelial cells (ECs) senescence and improving angiogenesis and osteogenesis. Dexamethasone (DEX) induces senescence of type H vascular ECs by promoting mitochondrial calcium overload mediated by mitochondrial-associated membranes (MAMs). ED-71 regulates glucose-regulated protein 75 (GRP75) through the vitamin D receptor (VDR)-protein kinase C (PKC) signaling pathway, reduces MAM-mediated mitochondrial calcium overload, inhibits senescence of ECs, and restores the angiogenesis-osteogenesis coupling mechanism, thereby ameliorating bone loss. This study reveals a new mechanism by which ED-71 ameliorates GIOP, by maintaining MAM-mediated mitochondrial calcium homeostasis to reduce vascular bone disease. This finding not only provides theoretical support for the application of ED-71 in the prevention and treatment of GIOP but also offers important theoretical basis for the development of MAM-targeted drugs for osteoporosis, as well as suggestions for potential therapeutic targets.