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.