Mechanism of estrogen regulating the senescence and osteogenic differentiation of bone marrow mesenchymal stem cells via the METTL3/SATB2 axis.
TL;DR
Estrogen regulates METTL3-mediated m6A modification to stabilize SATB2 mRNA via IGF2BP1, resulting in alleviated BMSC senescence and promoted OD, which provides a theoretical basis and potential intervention targets for BMSC-based anti-osteoporosis treatment strategies.
Abstract
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.