{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:59:32Z","timestamp":1780639172155,"version":"3.54.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      ObjectiveThis study aimed to explore the role of the\n                      <jats:italic>miR-21\/Mef2c\/Sost<\/jats:italic>\n                      pathway in the pathogenesis of diabetic osteoporosis (DOP) and to investigate whether metformin ameliorates DOP by regulating this signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We compared bone mineral density (BMD), bone turnover biomarkers, and bone miR-21 expression levels between elderly female patients with and without diabetes. Diabetic mice and high-glucose-treated MLO-Y4 osteocytes were used to explore the involvement of the\n                      <jats:italic>miR-21\/Mef2c\/Sost<\/jats:italic>\n                      pathway in DOP. miR-21 mice and MLO-Y4 osteocytes transfected with miR-21 mimics or inhibitors were utilized to verify the regulatory effect of the\n                      <jats:italic>Mef2c\/Sost<\/jats:italic>\n                      pathway on bone metabolism. Furthermore, we explored the therapeutic effect and underlying mechanism of metformin in improving DOP by targeting the\n                      <jats:italic>miR-21\/Mef2c\/Sost<\/jats:italic>\n                      pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Diabetic patients exhibited decreased bone miR-21 expression and reduced BMD, both of which were positively correlated with glycemic control status. Consistently, miR-21 was significantly downregulated in diabetic mice and high-glucose-cultured MLO-Y4 osteocytes. Both miR-21 and diabetic mice presented elevated protein levels of MEF2C and sclerostin, reduced expression of Cyclin D1 and RUNX2, as well as impaired bone strength and bone quality. As a direct target gene of miR-21,\n                      <jats:italic>Mef2c<\/jats:italic>\n                      was upregulated under high-glucose conditions, whereas its expression was reversed by miR-21 overexpression in MLO-Y4 osteocytes. The downstream gene Sost of\n                      <jats:italic>Mef2c<\/jats:italic>\n                      showed a consistent expression trend. Mechanically, metformin restored bone miR-21 expression in diabetic mice, increased the protein levels of Cyclin D1 and RUNX2 via inhibiting the\n                      <jats:italic>Mef2c\/Sost<\/jats:italic>\n                      pathway, and ultimately improved bone strength and bone quality in diabetic mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>miR-21\/Mef2c\/Sost<\/jats:italic>\n                      pathway critically contributes to DOP pathogenesis. Metformin improves bone health in diabetic mice by restoring miR-21 expression. This study is the first to demonstrate the association between metformin and the\n                      <jats:italic>miR-21\/Mef2c\/Sost<\/jats:italic>\n                      pathway in DOP, highlighting the skeletal protective effect of metformin beyond its glycemic regulation function and providing a novel therapeutic target for DOP treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1841140","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:00:37Z","timestamp":1780635637000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin attenuates diabetic osteoporosis via the miR-21 mediated Mef2c\/Sost pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Le","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Second Hospital of Tianjin Medical University","place":["Tianjin, 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