2. Academic Validation
  3. Eldecalcitol ameliorates type 2 diabetic osteoporosis by attenuating endothelial ferroptosis via the SOCE/O-GlcNAcylation axis

Eldecalcitol ameliorates type 2 diabetic osteoporosis by attenuating endothelial ferroptosis via the SOCE/O-GlcNAcylation axis

  • Free Radic Biol Med. 2025 Sep 24:241:447-458. doi: 10.1016/j.freeradbiomed.2025.09.041.
Yaling Dai 1,  Yujun Jiang 1,  Xiaolin Li 1,  Junyang Sun 1,  Hongrui Liu 2,  Bo Liu 3,  Minqi Li 4
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 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; Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, China.
  • 3 School of Clinical Medicine, Jining Medical University, Jining, China. Electronic address: liubo7230@mail.jnmc.edu.cn.
  • 4 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: liminqi@sdu.edu.cn.
PMID: 41005739 DOI: 10.1016/j.freeradbiomed.2025.09.041
Abstract

Accelerated bone degradation and increased risk of fractures, which lead to osteoporosis in patients, are common complications of type 2 diabetes (T2DM), severely impairing the quality of life of patients worldwide. Eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy) vitamin D3, or ED71) is a novel active vitamin D analog that has been used in the treatment of postmenopausal osteoporosis. However, its specific regulatory mechanism on endothelial cell function in the context of Ferroptosis, as well as its impact on osteogenesis-angiogenesis coupling in type 2 diabetic osteoporosis (T2DOP) remains unclear. The results showed that ED71 plays a role in the impaired osteogenesis and endothelial Ferroptosis induced by high glucose and high fat (HGHF), as evidenced by the changes in vascular proliferation, generation and migration, as well as the improvement of osteogenesis of bone marrow mesenchymal stem cells (BMSCs) and the decrease of endothelial ferrous ion (Fe2+) level, lipid peroxidation and mitochondrial membrane potential. In addition, ED71 treatment significantly alleviated the impaired osteogenesis and angiogenesis and decreased Ferroptosis markers in mouse T2DOP. When exploring the potential mechanism of action, we observed that ED71 suppressed Ferroptosis by rescuing store-operated calcium entry (SOCE) mediated calcium signaling and subsequently normalizing aberrant O-GlcNAcylation, and the introduction of the SOCE inhibitor 2-aminoethyl diphenylborinate (2APB) and the OGlcNAcylation inhibitor OSMI-1 counteracted the beneficial effects of ED71 in HGHF-treated endothelial cells. In conclusion, these data suggest that Ferroptosis of endothelial cells is associated with T2DOP, and ED71 can regulate Ferroptosis of endothelial cells through the SOCE/OGlcNActlation aixs, thereby targeting and modulating bone homeostasis.

Keywords

ED71; Ferroptosis; O-GlcNAcylation; SOCE; T2DOP; Type H vessel.

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