Mechanism of estrogen regulating the senescence and osteogenic differentiation of bone marrow mesenchymal stem cells via the METTL3/SATB2 axis.

OBJECTIVE: This article analyzes the mechanism by which estrogen affects bone marrow mesenchymal stem cell (BMSC) senescence and osteogenic differentiation (OD). METHODS: An osteoporosis mouse model was established using bilateral ovariectomy (OVX) and intervened with estradiol (E2) and a methyltransferase-like 3 (METTL3) inhibitor (STM2457). OVX-BMSCs were isolated from femoral tissues, characterized, and treated with lentivirus expressing sh-METTL3, sh-special AT-rich sequence-binding protein 2 (SATB2), oe-IGF2BP1, oe-SATB2, or negative controls (sh-NC and oe-NC) before OD induction and E2 treatment. N6-methyladenosine (m6A) modification sites were predicted by the SRAMP database, and the METTL3-SATB2 interaction was validated by a dual-luciferase reporter assay. m6A modification, mRNA stability, and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) enrichment were assessed by MeRIP-qPCR, actinomycin D, and RIP assays. RESULTS: OVX mice displayed bone loss, trabecular damage, and enhanced cell senescence, all reversed by estrogen. OVX-BMSCs had increased senescence and reduced OD potential, which were counteracted by estrogen. Mechanistically, estrogen upregulated METTL3 via ERα. Estrogen modulated METTL3-mediated m6A modification to facilitate SATB2 mRNA stability via IGF2BP1. Estrogen upregulated METTL3 to modulate BMSC senescence and OD via IGF2BP1/SATB2. Furthermore, inhibiting METTL3-mediated SATB2 m6A modification partly reversed the regulatory effect of estrogen on senescence and OD in OVX mice. CONCLUSIONS: Estrogen regulates METTL3-mediated m6A modification to stabilize SATB2 mRNA via IGF2BP1, resulting in alleviated BMSC senescence and promoted OD. This finding provides a theoretical basis and potential intervention targets for BMSC-based anti-osteoporosis treatment strategies. The modulation of bone resorption and bone turnover, not addressed in this study, requires further validation.