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Review
. 2025 Aug;241(8):e70080.
doi: 10.1111/apha.70080.

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

Jinpeng Wang  1 , Site Xu  1 , Yuchuan Xue  1 , Kaicheng Wen  1 , Mingzhe Sun  2 , Lin Tao  1
Affiliations
Review

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

Jinpeng Wang et al. Acta Physiol (Oxf). 2025 Aug.

Abstract

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.

Keywords: HBP; O‐GlcNAcylation; UDP‐GlcNAc; osteoporosis.

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