Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteoblast-triggered bone formation. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation and activity skew this balance resulting in progressive bone loss. O-GlcNAcylation is a posttranslational modification with attachment of a single O-linked β-D-N-acetylglucosamine (O-GlcNAc) residue to serine or threonine residues of target proteins. Although O-GlcNAcylation is one of the most common protein modifications, its role in bone homeostasis has not been systematically investigated. We demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during the early stages, whereas its downregulation is required for osteoclast maturation. At the molecular level, O-GlcNAcylation affects several pathways including oxidative phosphorylation and cell-cell fusion. TNFα fosters the dynamic regulation of O-GlcNAcylation to promote osteoclastogenesis in inflammatory arthritis. Targeted pharmaceutical or genetic inhibition of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) arrests osteoclast differentiation during early stages of differentiation and during later maturation, respectively, and ameliorates bone loss in experimental arthritis. Knockdown of NUP153, an O-GlcNAcylation target, has similar effects as OGT inhibition and inhibits osteoclastogenesis. These findings highlight an important role of O-GlcNAcylation in osteoclastogenesis and may offer the potential to therapeutically interfere with pathologic bone resorption.

骨量通过破骨细胞诱导的骨吸收和成骨细胞触发的骨形成之间的平衡来维持。然而，在类风湿性关节炎 (RA) 等炎症性关节炎中，破骨细胞分化和活性的增加会扭曲这种平衡，导致进行性骨质流失。O-GlcNAcylation 是一种翻译后修饰，将单个 O-连接的 β-DN-乙酰氨基葡萄糖 (O-GlcNAc) 残基连接到靶蛋白的丝氨酸或苏氨酸残基上。尽管 O-GlcNAcylation 是最常见的蛋白质修饰之一，但其在骨稳态中的作用尚未得到系统研究。我们证明破骨细胞生成需要 O-GlcNAcylation 的动态变化。增加的 O-GlcNAcylation 在早期促进破骨细胞分化，而它的下调是破骨细胞成熟所必需的。在分子水平上，O-GlcNAcylation 影响多种途径，包括氧化磷酸化和细胞-细胞融合。TNFα 促进 O-GlcNAcylation 的动态调节，以促进炎症性关节炎中的破骨细胞生成。O-GlcNAc 转移酶 (OGT) 或 O-GlcNAcase (OGA) 的靶向药物或基因抑制分别在分化早期和成熟后期阻止破骨细胞分化，并改善实验性关节炎的骨丢失。敲除 NUP153（一种 O-GlcNAcylation 靶标）具有与 OGT 抑制相似的作用并抑制破骨细胞生成。