Life sciences · 2026
Glucocorticoid-induced METTL3 promotes SONFH by enhancing MEG3 m6A methylation and subsequent ABL2 upregulation.
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Wang Linxiang, Meng Hongming, Shou Zeyu, Bai Zhibiao, Chen Chun, Huang Xiaojing
Аннотация
BACKGROUND: Steroid-induced osteonecrosis of the femoral head (SONFH) is a refractory orthopedic disease. While N6-methyladenosine (m6A) modification is implicated in bone metabolism, its specific role and mechanism in SONFH pathogenesis require further elucidation.
METHODS: Bioinformatics analysis identified key m6A-related genes. Two-sample Mendelian randomization (MR) analysis assessed causal relationships. In vitro, dexamethasone-treated bone marrow mesenchymal stem cells (BMSCs) and gain/loss-of-function experiments were used to investigate the potential regulatory axis. An in vivo mouse SONFH model was established for pathological and molecular confirmation.
RESULTS: METTL3 was identified as a crucial upregulated m6A "writer" in SONFH. MR indicated causal links between MEG3, ABL2, and SONFH. Dexamethasone elevated METTL3 expression, which enhanced m6A methylation and stability of the long non-coding RNA MEG3. Upregulated MEG3 was positively correlated with increased ABL2 expression, which was accompanied by suppressed osteogenesis and promoted adipogenesis in BMSCs. Knockdown of METTL3 or MEG3 reversed these effects, while MEG3 overexpression rescued the phenotype caused by METTL3 inhibition. In mice, METTL3 knockdown alleviated femoral head necrosis, reduced apoptosis, and downregulated the MEG3/ABL2 axis.
CONCLUSION: This study reveals a novel glucocorticoid/METTL3/MEG3/ABL2 pathway in SONFH, where METTL3-mediated m6A modification of MEG3 disrupts BMSC differentiation balance in association with ABL2 upregulation. These findings provide new insights into SONFH pathogenesis and highlight potential therapeutic targets.
METHODS: Bioinformatics analysis identified key m6A-related genes. Two-sample Mendelian randomization (MR) analysis assessed causal relationships. In vitro, dexamethasone-treated bone marrow mesenchymal stem cells (BMSCs) and gain/loss-of-function experiments were used to investigate the potential regulatory axis. An in vivo mouse SONFH model was established for pathological and molecular confirmation.
RESULTS: METTL3 was identified as a crucial upregulated m6A "writer" in SONFH. MR indicated causal links between MEG3, ABL2, and SONFH. Dexamethasone elevated METTL3 expression, which enhanced m6A methylation and stability of the long non-coding RNA MEG3. Upregulated MEG3 was positively correlated with increased ABL2 expression, which was accompanied by suppressed osteogenesis and promoted adipogenesis in BMSCs. Knockdown of METTL3 or MEG3 reversed these effects, while MEG3 overexpression rescued the phenotype caused by METTL3 inhibition. In mice, METTL3 knockdown alleviated femoral head necrosis, reduced apoptosis, and downregulated the MEG3/ABL2 axis.
CONCLUSION: This study reveals a novel glucocorticoid/METTL3/MEG3/ABL2 pathway in SONFH, where METTL3-mediated m6A modification of MEG3 disrupts BMSC differentiation balance in association with ABL2 upregulation. These findings provide new insights into SONFH pathogenesis and highlight potential therapeutic targets.