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While aberrant\n                      <jats:italic>H19<\/jats:italic>\n                      promoter methylation and expression have been linked to various bone metabolic disorders such as osteoporosis and osteosarcoma, their specific role in the pathogenesis of GC-induced ONFH remains largely unexplored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed\n                      <jats:italic>H19<\/jats:italic>\n                      promoter methylation,\n                      <jats:italic>DNMTs<\/jats:italic>\n                      , and\n                      <jats:italic>H19<\/jats:italic>\n                      expression in human ONFH BMSCs. Roles of\n                      <jats:italic>Dnmt1<\/jats:italic>\n                      and\n                      <jats:italic>H19<\/jats:italic>\n                      in osteogenic\/adipogenic differentiation were assessed using staining (Alizarin Red\/Oil Red O) and pathway analysis. Effects of\n                      <jats:italic>Dnmt1<\/jats:italic>\n                      knockdown or\n                      <jats:italic>H19<\/jats:italic>\n                      overexpression were tested via BMSC implantation in a GC-induced ONFH rat model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>H19<\/jats:italic>\n                      promoter hypomethylation caused\n                      <jats:italic>H19<\/jats:italic>\n                      overexpression in undifferentiated GC-ONFH BMSCs; expression decreased upon differentiation.\n                      <jats:italic>H19<\/jats:italic>\n                      and\n                      <jats:italic>Dnmt1<\/jats:italic>\n                      expression were negatively correlated.\n                      <jats:italic>Dnmt1<\/jats:italic>\n                      predominated among\n                      <jats:italic>DNMTs<\/jats:italic>\n                      in epigenetically regulating\n                      <jats:italic>H19<\/jats:italic>\n                      and reciprocally modulated differentiation (inhibiting osteogenesis, promoting adipogenesis). Conversely,\n                      <jats:italic>H19<\/jats:italic>\n                      promoted osteogenesis and inhibited adipogenesis by suppressing\n                      <jats:italic>GSK-3\u03b2<\/jats:italic>\n                      , activating Wnt\/\u03b2-catenin signaling. In the rat model, implanted BMSCs with\n                      <jats:italic>Dnmt1<\/jats:italic>\n                      knockdown or\n                      <jats:italic>H19<\/jats:italic>\n                      overexpression reduced empty lacunae, corrected the osteo-adipogenic imbalance, and delayed progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>Dnmt1<\/jats:italic>\n                      \/\n                      <jats:italic>H19<\/jats:italic>\n                      \/\n                      <jats:italic>GSK-3\u03b2<\/jats:italic>\n                      axis reciprocally regulates BMSC osteogenic and adipogenic differentiation in GC-induced ONFH, representing a novel epigenetic mechanism underlying GC-induced ONFH and a promising MSC-based therapeutic strategy for early-stage disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0345372","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T17:33:56Z","timestamp":1774632836000},"page":"e0345372","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Glucocorticoid-Induced alterations in DNA methylation in the H19 promoter of Bone Marrow-Derived Mesenchymal Stem Cells are associated with the pathogenesis of osteonecrosis"],"prefix":"10.1371","volume":"21","author":[{"given":"Song","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhi","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangtao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2570-5897","authenticated-orcid":true,"given":"Weihua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"pone.0345372.ref001","first-page":"12","article-title":"Nontraumatic avascular necrosis of the femoral head. 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