Metformin attenuates diabetic osteoporosis via the miR-21 mediated Mef2c/Sost pathway

ObjectiveThis study aimed to explore the role of the miR-21/Mef2c/Sost pathway in the pathogenesis of diabetic osteoporosis (DOP) and to investigate whether metformin ameliorates DOP by regulating this signaling pathway.

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 miR-21/Mef2c/Sost 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 Mef2c/Sost pathway on bone metabolism. Furthermore, we explored the therapeutic effect and underlying mechanism of metformin in improving DOP by targeting the miR-21/Mef2c/Sost pathway.

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, Mef2c was upregulated under high-glucose conditions, whereas its expression was reversed by miR-21 overexpression in MLO-Y4 osteocytes. The downstream gene Sost of Mef2c 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 Mef2c/Sost pathway, and ultimately improved bone strength and bone quality in diabetic mice.

The miR-21/Mef2c/Sost 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 miR-21/Mef2c/Sost pathway in DOP, highlighting the skeletal protective effect of metformin beyond its glycemic regulation function and providing a novel therapeutic target for DOP treatment.