1. Academic Validation
  2. O-GlcNAcylation in Gli1+ Mesenchymal Stem Cells Is Indispensable for Bone Formation and Fracture Healing

O-GlcNAcylation in Gli1+ Mesenchymal Stem Cells Is Indispensable for Bone Formation and Fracture Healing

  • Int J Mol Sci. 2025 Mar 18;26(6):2712. doi: 10.3390/ijms26062712.
Moyu Liu 1 Yujie Hu 1 2 Chengjia You 1 Ding Xiong 1 Ling Ye 1 2 Yu Shi 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
  • 2 Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Abstract

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.

Keywords

Gli1+ MSCs; O-GlcNAcylation; OGT; bone formation; fracture repair; hedgehog signaling.

Figures
Products