Elabela APJ Axis attenuates type II diabetes osteoporosis by enhancing the coupling of H-type angiogenesis and osteogenesis

  • Int Immunopharmacol. 2026 Feb 1:170:116068. doi: 10.1016/j.intimp.2025.116068.
Run-Xun Ma  1 ,  Yang-Fan Guo  1 ,  Si-Xiang Feng  1 ,  Yi-Xun Huang  1 ,  Li-Bo Pan  1 ,  Yi-Tian Bu  1 ,  Yi-Kai Wang  1 ,  Jian Luo  2 ,  Bing-Hao Lin  3 ,  Lei Yang  4
Affiliations
  • 1. Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China.
  • 2. Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, China.
  • 3. Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China. Electronic address: [email protected].
  • 4. Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China; Wenzhou Key Laboratory of Osteoporosis and Elderly Bone Health, Wenzhou, China. Electronic address: [email protected].
PMID: 41455365 DOI: 10.1016/j.intimp.2025.116068
Abstract

Background: Type 2 diabetes-related osteoporosis (T2DOP) is intricately connected to microvascular degeneration, particularly the loss of H-type vessels involved in osteogenesis-angiogenesis coupling. Elabela (ELA), a crucial APJ receptor ligand, regulates vascular development, yet its specific role in the diabetic bone microenvironment remains undefined. This study investigates whether ELA restoring H-type vessel formation and vascular-bone coupling offers a therapeutic strategy for T2DOP.

Methods: A T2DOP mouse model was established using a high-fat diet combined with low-dose streptozotocin (STZ) injection. Bone microarchitecture and vasculature were assessed via micro-CT and immunofluorescence. In vitro, bone marrow endothelial cells (BMECs) were subjected to high-glucose and high-fat (HGHF) stress and co-cultured with MC3T3-E1 osteoblasts in a Transwell system to evaluate vascular-bone coupling. The role of the ELA-APJ axis was interrogated using exogenous ELA peptide (1 mg/kg/day in vivo; 5 μM in vitro) and the specific APJ inhibitor ML221.

Results: T2DOP mice exhibited significantly reduced femoral H-type vessel density and downregulated ELA expression compared to controls. ELA administration significantly reversed bone loss, increasing bone volume fraction (BV/TV) by 10.3 % ((p < 0.01))and trabecular number (Tb.N) by 1.8/mm (p < 0.05). Mechanistically, ELA treatment rescued HGHF-impaired BMEC migration and tube formation In the co-culture system, ELA-stimulated BMECs enhanced osteogenic differentiation in MC3T3-E1 cells, indicated by elevated ALP activity and mineralization. Critically, these protective effects were abolished by the APJ inhibitor ML221, confirming that ELA activates the HIF-1α/VEGF/Notch1/Noggin signaling cascade to restore angiocrine function.

Conclusion: The ELA/APJ axis is a critical regulator of the bone vascular niche. ELA treatment attenuates T2DOP by promoting H-type vessel formation and re-coupling osteogenes.

Keywords
APJ; Angiogenic-osteogenic coupling; Elabela; HIF-1α/VEGF/Notch1/noggin signaling pathways; Mice; Type 2 diabetic osteoporosis; Type H vessels.
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