ArticlePloS one2026
MMP-2 associated imbalance of VEGF/Endostatin is linked to suppression of the PI3K/AKT/HIF-1α pathway in steroid-induced osteonecrosis of femoral head.
Article in PloS one, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveTo investigate the role of matrix metalloproteinase-2 (MMP-2) and the imbalance between vascular endothelial growth factor (VEGF) and Endostatin in the pathogenesis of steroid-induced osteonecrosis of femoral head (SONFH).
methodsClinical samples and animal models were combined to systematically analyze the impact of VEGF/Endostatin imbalance on angiogenesis and osteogenesis. Clinical samples from SONFH patients and femoral neck fracture controls were analyzed for VEGF, Endostatin and MMP-2 expression. The SONFH model in C57BL/6J mice was established to evaluate the effects of an imbalanced VEGF/Endostatin axis on angiogenesis and osteogenesis, assessed by micro-CT based vascular imaging, calcein labeling, and bone density analysis. MMP-2 intervention experiments were conducted to explore its role in the VEGF/Endostatin ratio.
resultsClinical data revealed significantly lower VEGF/Endostatin ratio (P < 0.001) and higher MMP-2 levels (P < 0.05) in necrotic regions of SONFH patients compared to the controls. In animal models, decreased VEGF/Endostatin ratio caused by Endostatin supplementation could further suppress angiogenesis and osteogenesis (P < 0.05). Mechanistically, MMP‑2 disrupts the VEGF/Endostatin balance by decreasing VEGF expression (P < 0.05) and increasing Endostatin levels (P < 0.05), which is associated with the suppression of PI3K/AKT/HIF‑1α pathway.
conclusionsOur findings reveal that the imbalance of VEGF/Endostatin is a key driver of SONFH through impaired angiogenesis and osteogenesis. We further demonstrate that MMP‑2 contributes to this imbalance, likely linked to suppression of the PI3K/AKT/HIF‑1α pathway. These results support the VEGF/Endostatin ratio as a potential diagnostic biomarker and suggest that targeting MMP‑2 or Endostatin may represent promising therapeutic strategies.
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