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

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

  • Cell Signal. 2025 Dec 8:139:112298. doi: 10.1016/j.cellsig.2025.112298.
Xiaorui Wang 1,  Weidong Zhang 1,  Ting Liu 1,  Xing Rong 1,  Qinghua Ren 1,  Shibing Guan 2,  Minqi Li 3
Affiliations

Affiliations

  • 1 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.
  • 2 Department of Hand and Foot Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China. Electronic address: [email protected].
  • 3 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China; Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China; School of Clinical Medicine, Jining Medical University, Jining, China. Electronic address: [email protected].
PMID: 41371564 DOI: 10.1016/j.cellsig.2025.112298
Abstract

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.

Keywords

ED-71; GIOP; MAMs; Mitochondrial calcium overload; Senescence; Type-H blood vessel; Vascularized osteogenesis.

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