{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T18:03:06Z","timestamp":1776448986239,"version":"3.51.2"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["xzy012025125"],"award-info":[{"award-number":["xzy012025125"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Clinical data revealed significantly lower VEGF\/Endostatin ratio (P\u2009&lt;\u20090.001) and higher MMP-2 levels (P\u2009&lt;\u20090.05) 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\u2009&lt;\u20090.05). Mechanistically, MMP\u20112 disrupts the VEGF\/Endostatin balance by decreasing VEGF expression (P\u2009&lt;\u20090.05) and increasing Endostatin levels (P\u2009&lt;\u20090.05), which is associated with the suppression of PI3K\/AKT\/HIF\u20111\u03b1 pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal that the imbalance of VEGF\/Endostatin is a key driver of SONFH through impaired angiogenesis and osteogenesis. We further demonstrate that MMP\u20112 contributes to this imbalance, likely linked to suppression of the PI3K\/AKT\/HIF\u20111\u03b1 pathway. These results support the VEGF\/Endostatin ratio as a potential diagnostic biomarker and suggest that targeting MMP\u20112 or Endostatin may represent promising therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0346880","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T17:28:41Z","timestamp":1776446921000},"page":"e0346880","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["MMP-2 associated imbalance of VEGF\/Endostatin is linked to suppression of the PI3K\/AKT\/HIF-1\u03b1 pathway in steroid-induced osteonecrosis of femoral 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