Characterization of the role of O-GlcNAcylation in osteoclastogenesis

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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.