Retinoic acid impairs the osteogenic differentiation of BMSCs via the miR-486/FOXO1 axis: a therapeutic target for bone loss.

Retinoic acid (RA), a bioactive vitamin A metabolite, is widely recognized for promoting bone loss and inducing osteoporosis, but its underlying mechanisms remain incompletely understood. This study demonstrated that the expression of miR-486-5p is significantly upregulated in RA-treated human bone marrow mesenchymal stem cells (hBMSCs). The overexpression of miR-486-5p markedly inhibited osteogenic differentiation, whereas its inhibition enhanced osteogenic differentiation. Using dual-luciferase reporter assays and Western blot analysis, we confirmed that miR-486-5p directly targets and suppresses FOXO1 expression, thereby impairing osteogenic differentiation. Furthermore, we developed a composite gelatin methacryloyl (GelMA) hydrogel system incorporating porous starch, which improves the mechanical strength and hemostatic adsorption capacity of the hydrogel. The porous starch component accelerated both in vitro and in vivo blood coagulation and enabled more effective small molecule sustained-release in GelMA. Crucially, loading the starch/GelMA hydrogel with antagomiR-486-5p greatly improved bone defect repair. This effect was achieved by inhibiting miR-486-5p activity in vivo. In conclusion, our research reveals a novel pathway through which RA inhibits osteogenesis by the miR-486-5p/FOXO1 axis, providing deeper mechanistic insight into bone metabolism. The starch/GelMA hydrogel serves as an effective miRNA drug carrier for bone defect treatment, establishing a novel therapeutic strategy for bone loss involving targeted modulation of the miR-486-5p/FOXO1 pathway.