A novel miRNA-TF-mRNA regulatory network associated with cellular senescence in osteoporosis

Summary This study investigated the role of miR-22-3p/ESR1 axis in osteoporosis (OP) pathogenesis. Bioinformatics analysis of OP datasets and patient bone marrow samples revealed significant upregulation of miR-22-3p accompanied by downregulation of ESR1. Mechanistic validation via dual-luciferase reporter assays, RNA pull-down, and molecular docking confirmed that miR-22-3p directly targets and suppresses ESR1 expression. Functional in vitro assays in human bone marrow mesenchymal stem cells (hBMSCs) demonstrated that miR-22-3p overexpression accelerated both cellular senescence (CS) and adipogenic differentiation. Notably, this effect was reversed by ESR1 overexpression. In an aged mouse model, local intra-bone marrow administration of a miR-22-3p inhibitor effectively reduced bone marrow mesenchymal stem cell (BMSC) senescence, improved bone microstructure, and attenuated OP progression. These findings establish that the miR-22-3p-ESR1 regulatory axis critically drives OP development by coordinately promoting CS and adipogenic differentiation while suppressing osteogenesis. This pathway provides a promising mechanistic foundation for future therapeutic strategies targeting OP.