Emerging Roles of Protein O‐GlcNAcylation in Bone Remodeling: New Insights Into Osteoporosis

Background Bone is a dynamic tissue undergoing constant remodeling mediated by osteoblasts and osteoclasts. An imbalance between these cells can lead to reduced bone mass, disrupted microarchitecture, and ultimately osteoporosis. O‐GlcNAcylation is a dynamic and reversible posttranslational modification where uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) is added or removed from serine/threonine residues of proteins by OGT and OGA, respectively. Emerging evidence indicates that appropriate O‐GlcNAcylation is essential for bone remodeling, although its specific effects remain controversial. Aims This review aims to summarize the process of O‐GlcNAcylation and critically evaluate its specific effects on osteoblast‐mediated and osteoclast‐mediated bone remodeling. Materials & Methods Based on a comprehensive analysis of published scientific literature, we synthesized the current evidence regarding the role of O‐GlcNAcylation in bone cell differentiation and function, and its association with osteoporosis. Results Our analysis reveals that cellular demands for O‐GlcNAcylation vary during osteoblastic and osteoclastic differentiation. Moderate O‐GlcNAcylation is essential for osteoblast differentiation, whereas dynamic alterations in O‐GlcNAcylation are crucial for osteoclast differentiation. Furthermore, elevated O‐GlcNAcylation levels are consistently observed in both primary and secondary osteoporosis cases, suggesting a potential pathogenic role in the dysregulation of bone remodeling. Discussion These findings indicate that the effects of O‐GlcNAcylation are cell type‐ and differentiation stage‐dependent in bone. The observed elevation of O‐GlcNAcylation in osteoporosis underscores its potential contribution to the dysregulation of bone remodeling pathways. Conclusion This review provides novel mechanistic insights into osteoporosis pathogenesis via dysregulation of the O‐GlcNAcylation post‐translational modification. Understanding these mechanisms will facilitate the development of novel therapeutic strategies targeting O‐GlcNAcylation to restore balanced bone remodeling.