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

• Published in: Bone Research Vol. 10; no. 1; p. 51
• Main Authors: Li, Yi-Nan, Chen, Chih-Wei, Trinh-Minh, Thuong, Zhu, Honglin, Matei, Alexandru-Emil, Györfi, Andrea-Hermina, Kuwert, Frederic, Hubel, Philipp, Ding, Xiao, Manh, Cuong Tran, Xu, Xiaohan, Liebel, Christoph, Fedorchenko, Vladyslav, Liang, Ruifang, Huang, Kaiyue, Pfannstiel, Jens, Huang, Min-Chuan, Lin, Neng-Yu, Ramming, Andreas, Schett, Georg, Distler, Jörg H. W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.07.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/443/63; 692/699; Homeostasis; Internal Medicine; Medicine; Medicine & Public Health; Orthopedics; Pathogenesis; Phosphorylation; Proteins; Regulation; Rheumatoid arthritis; Rheumatology
• ISSN: 2095-4700; 2095-6231
• DOI: 10.1038/s41413-022-00218-9

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.