Characterization of the role of O-GlcNAcylation in osteoclastogenesis

在生理条件下，骨量由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，破骨细胞分化增加会扭曲这种平衡，导致进行性骨丢失。O-GlcN酰化是一种翻译后修饰，将一个O-连接的β-D-N-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。虽然O-GlcN酰化是最常见的蛋白质修饰之一，但它在骨稳态中的作用尚未得到系统的研究。在我们的初步结果中，我们证明了O-GlcN酰化的动态变化是破骨细胞发生所必需的。在破骨细胞形成的早期阶段，增加的O-GlcN酰化促进破骨细胞分化，而它的下调是破骨细胞成熟所必需的。肿瘤坏死因子α在炎性关节炎中促进O-GlcN酰化的动态调节，促进破骨细胞的形成。靶向药物或基因抑制O-GlcNAc转移酶(OGT)或O-GlcNAcase(OGA)分别在分化早期和成熟期阻止破骨细胞分化，并改善实验性关节炎局部和全身的骨丢失。随着目前的项目应用，我们的目标是进一步研究O-GlcN酰化在破骨细胞形成中的作用。具体地说，我们计划研究O-GlcN酰化调控破骨细胞生成的分子机制，研究O-GlcN酰化在破骨细胞前体循环中作为生物标志物的作用，研究O-GlcN酰化在破骨细胞生成中的作用，探讨O-GlcN酰化在非炎症性骨丢失中的作用，以及O-GlcN酰化在高血糖诱导的破骨细胞生成中的作用。

Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteo-blast-triggered bone formation in physiological conditions. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation skews 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. In our preliminary results, we demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during early stages of osteoclastogenesis, whereas its downregulation is required for osteoclast maturation. Tumor necrosis factor α (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 local and systemic bone loss in experimental arthritis. With the current project application, we aim to investigate further the role of O-GlcNAcylation in osteoclastogenesis. Specifically, we plan to characterize the molecular mechanisms by which O-GlcNAcylation regulates osteoclastogenesis, to study the utility of O-GlcNAcylation in circulating osteoclast precursors as biomarkers, to investigate the role of O-GlcNAcylation on osteoclastogenesis in non-inflammatory bone loss and to explore the role of O-GlcNAcylation in hyperglycemia-induced acceleration of osteoclastogenesis.