Liu Moyu, Hu Yujie, You Chengjia, Xiong Ding, Ye Ling, Shi Yu
State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Int J Mol Sci. 2025 Mar 18;26(6):2712. doi: 10.3390/ijms26062712.
Adult mesenchymal stem cells (MSCs) play a crucial role in maintaining bone health and promoting regeneration. In our previous research, we identified Gli1 MSCs as key contributors to the formation of most trabecular bone in adulthood and as essential for healing bicortical fractures. However, the mechanisms behind the maintenance and differentiation of Gli1 MSCs are still not fully understood. O-linked N-acetylglucosamine modification (O-GlcNAcylation), mediated by O-GlcNAc glycosyltransferase (OGT), is involved in various biological processes and diseases. Our earlier work also demonstrated that O-GlcNAcylation is necessary for Wnt-stimulated bone formation. Nonetheless, the specific functions of O-GlcNAcylation in MSCs have not been completely elucidated. In this study, we found that the absence of OGT in Gli1 MSCs led to a decrease in O-GlcNAcylation, which impaired both the bone formation and regeneration following fractures. Mechanistically, the Hedgehog signaling pathway induced O-GlcNAcylation through the insulin-like growth factor (Igf)-mTORC2 axis. This process stabilized the Gli2 protein at a specific site Ser355 and promoted osteogenesis in MSCs in vitro. Our findings reveal a significant mechanism by which O-GlcNAcylation regulates bone development and repair in mammals.
成人间充质干细胞（MSCs）在维持骨骼健康和促进再生方面发挥着关键作用。在我们之前的研究中，我们确定Gli1间充质干细胞是成年期大多数小梁骨形成的关键贡献者，也是双皮质骨折愈合所必需的。然而，Gli1间充质干细胞维持和分化背后的机制仍未完全了解。由O-连接N-乙酰葡糖胺糖基转移酶（OGT）介导的O-连接N-乙酰葡糖胺修饰（O-GlcNAcylation）参与各种生物过程和疾病。我们早期的工作还表明，O-GlcNAcylation是Wnt刺激的骨形成所必需的。尽管如此，O-GlcNAcylation在间充质干细胞中的具体功能尚未完全阐明。在这项研究中，我们发现Gli1间充质干细胞中OGT的缺失导致O-GlcNAcylation减少，这损害了骨折后的骨形成和再生。从机制上讲，刺猬信号通路通过胰岛素样生长因子（Igf）-mTORC2轴诱导O-GlcNAcylation。这一过程在特定位点Ser355稳定Gli2蛋白，并促进体外间充质干细胞的成骨作用。我们的研究结果揭示了一种重要机制，通过该机制O-GlcNAcylation调节哺乳动物的骨骼发育和修复。
