Wang Yantong, Cao Yangyang, Fan Zhipeng
Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing 100050, China.
Department of General Dentistry and Integrated Emergency Dental Care, Capital Medical University School of Stomatology, Beijing, China.
Stem Cells Transl Med. 2025 Jun 25;14(7). doi: 10.1093/stcltm/szaf024.
Postmenopausal osteoporosis, a prevalent metabolic bone disease, elevates susceptibility to fragility fractures while imposing substantial healthcare costs and public health challenges. The profound interplay between BMSCs and surrounding extracellular matrix (ECM) proteins, which are highly rich in O-GlcNAcylation, play pivotal roles in the process of osteoporosis. M6A methylation plays a crucial regulatory role in the development of osteoporosis, while the crosstalk between m6A methylation and ECM O-GlcNAcylation remains mechanistically undefined. Here we found Mettl7a overexpression improved the impaired osteogenic capability of OVX-mBMSCs in vitro. Conditional knockout of Mettl7a in the mesenchyme (Prx1-cre;Mettl7af/f) accelerated bone loss of OVX mice. Mechanistically, Mettl7a promoted mBMSCs osteogenic differentiation by targeting the O-GlcNAcylation of Bsp, an ECM protein. Mettl7a regulated the expression and O-GlcNAcylation of Bsp through m6A methylation of Oga. We further demonstrated that Mettl7a-AAV treatment alleviated bone loss phenotype in osteoporosis mice via the O-GlcNAcylation of Bsp. Collectively, our findings reveal novel mechanistic intersections between ECM protein O-GlcNAcylation and m6A methylation, advancing the understanding of osteoporotic regulation.
绝经后骨质疏松症是一种常见的代谢性骨病，它增加了脆性骨折的易感性，同时带来了巨大的医疗成本和公共卫生挑战。骨髓间充质干细胞（BMSCs）与富含O-连接的N-乙酰葡糖胺（O-GlcNAcylation）的周围细胞外基质（ECM）蛋白之间的深刻相互作用在骨质疏松症过程中起关键作用。m6A甲基化在骨质疏松症的发展中起关键调节作用，而m6A甲基化与ECM O-GlcNAcylation之间的串扰在机制上仍不明确。在此，我们发现Mettl7a过表达改善了去卵巢小鼠骨髓间充质干细胞（OVX-mBMSCs）体外受损的成骨能力。在间充质中条件性敲除Mettl7a（Prx1-cre;Mettl7af/f）加速了去卵巢小鼠的骨质流失。机制上，Mettl7a通过靶向ECM蛋白骨唾液酸蛋白（Bsp）的O-GlcNAcylation促进mBMSCs成骨分化。Mettl7a通过Oga的m6A甲基化调节Bsp的表达和O-GlcNAcylation。我们进一步证明，Mettl7a腺相关病毒（AAV）治疗通过Bsp的O-GlcNAcylation减轻了骨质疏松症小鼠的骨质流失表型。总之，我们的发现揭示了ECM蛋白O-GlcNAcylation与m6A甲基化之间新的机制交叉点，推进了对骨质疏松症调节的理解。
