2. Academic Validation
  3. Glucocorticoid impairs angiogenesis-dependent osteogenesis by downregulating EphB4 in endothelial cells

Glucocorticoid impairs angiogenesis-dependent osteogenesis by downregulating EphB4 in endothelial cells

  • Biochem Pharmacol. 2026 Feb:244:117586. doi: 10.1016/j.bcp.2025.117586.
Qinghua Ren 1,  Xing Rong 1,  Ting Liu 1,  Zhichao Zhang 1,  Weidong Zhang 1,  Hongrui Liu 2,  Shibing Guan 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, Jinan, China.
  • 3 Department of Hand and Foot Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China. Electronic address: [email protected].
  • 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: [email protected].
PMID: 41344513 DOI: 10.1016/j.bcp.2025.117586
Abstract

Long-term or high-dose glucocorticoids (GCs) exposure leads to rapid bone loss and microarchitectural deterioration, ultimately resulting in glucocorticoid-induced osteoporosis (GIOP). Although the progression of GIOP is closely associated with impaired type H blood vessel function, the underlying mechanisms remain insufficiently defined. Using a dexamethasone (DEX)-induced GIOP mouse model, we observed a simultaneous reduction in type H blood vessels and Ephrin type-B receptor 4 (EphB4) expression. Co-culture of bone marrow mesenchymal stem cells (BMSCs) with endothelial cells (ECs) overexpressing EphB4 confirmed that endothelial EphB4 is a critical regulator of angiogenesis-dependent osteogenesis, a process disrupted by DEX-mediated EphB4 downregulation. Specifically, DEX-induced EphB4 downregulation induced cellular senescence in ECs, and the resulting senescence-associated secretory phenotype (SASP) may further impair BMSC osteogenic differentiation. We additionally observed that diminished EphB4-EphrinB2 crosstalk between ECs and BMSCs may further exacerbate osteogenesis. The Wnt/β-catenin pathway was identified as a critical mediator through which DEX inhibits EphB4 expression in ECs. Collectively, these findings reveal a previously unrecognized EphB4-mediated mechanism contributing to GIOP pathogenesis and provide mechanistic insight into potential therapeutic strategies targeting angiogenesis-osteogenesis coupling.

Keywords

BMSC; Endothelial cell; EphB4; Glucocorticoid-induced osteoporosis; Senescence; Type H blood vessels.

Figures
Products