Jing Zhang, Kun Tian, Nan Zhuang, Xin‐kui Zhang, Yanling Zhang
O-GlcNAc glycosylation may provide a novel approach for restoring bone homeostasis in skeletal diseases.
BACKGROUND: O-GlcNAcylation is a dynamic and reversible post-translational modification of serine/threonine residues on cytoplasmic and nuclear proteins. Although it has been implicated as a "differentiation switch and functional regulator" in osteoclast biology, a systematic synthesis of its role across the macrophage-osteoclast axis and its contribution to bone remodeling disorders has not been elucidated. METHODS: The present study examines evidence on O-GlcNAc cycling in macrophage polarization, RANKL signaling amplification, and the maintenance of the osteoclast transcriptional program. The analysis integrates findings from cellular and molecular studies with clinical evidence from diseases such as osteoporosis, inflammatory bone destruction, and tumor bone metastasis to provide a comprehensive overview of the underlying mechanisms. RESULTS: O-GlcNAcylation is emerging as a pivotal regulator that disrupts bone remodeling equilibrium through multiple interconnected mechanisms along the macrophage-osteoclast axis. It promotes polarization of pro-inflammatory macrophages, amplifies RANKL-mediated signaling cascades, and stabilizes the transcriptional programs that drive osteoclast differentiation and function. CONCLUSION: O-GlcNAc glycosylation may provide a novel approach for restoring bone homeostasis in skeletal diseases.