Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153

Abstract

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.

Effect of Anti‐S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis–Specific Transcriptional Signatures in Human Skin

“…Immunofluorescence staining was performed as described previously. 19 The expression of pSTAT3 was visualized by staining with rabbit anti-pSTAT3 (#9145S; Cell Signaling Technology) at a dilution of 1:200 in 2% BSA/DPBS. The expression of tenascin-C was visualized by staining with mouse anti-T2H5 (#ab3970; Abcam) at a dilution of 1:500 in 2% BSA/DPBS.…”

“…Immunofluorescence staining was performed as described previously 19 . The expression of pSTAT3 was visualized by staining with rabbit anti‐pSTAT3 (#9145S; Cell Signaling Technology) at a dilution of 1:200 in 2% BSA/DPBS.…”

O-GlcNAcylation: roles and potential therapeutic target for bone pathophysiology

“…Tumor necrosis factor alpha (TNF-α), a key mediator of inflammation in arthritis, fosters the dynamic regulation of O-GlcNAcylation during osteoclastogenesis [ 76 ]. Mechanically, TNF-α enhances osteoclastogenesis in inflammatory arthritis by increasing the expression levels of OGT and OGA.…”

Bioactives and Biomaterial Construction for Modulating Osteoclast Activities

“…This approach impacts various processes, including cytokine signaling, oxidative phosphorylation, actin cytoskeleton dynamics, and cell–cell fusion, resulting in a significant inhibition of osteoclastogenesis. [ 24 ]…”

“…This approach impacts various processes, including cytokine signaling, oxidative phosphorylation, actin cytoskeleton dynamics, and cell-cell fusion, resulting in a significant inhibition of osteoclastogenesis. [24] As a result, targeted drugs or gene inhibition of O-GlcNAc transferase and O-GlcNA enzyme have shown promise. Examples include pharmacological inhibitors like OSMI-1 and Thiamet-G.…”