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

Yi-Nan Li, Chih-Wei Chen, Thuong Trinh-Minh, Honglin Zhu, Alexandru-Emil Matei, Andrea-Hermina Györfi, Frederic Kuwert, Philipp Hubel, Xiao Ding, Cuong Tran Manh, Xiaohan Xu, Christoph Liebel (+8 others)
2022 Zenodo  

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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
more » ... ation 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. Disruption of the O-GlcNAcylation target NUP153 phenocopies 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.
doi:10.5281/zenodo.6580968 fatcat:rpr44g3vk5cljpilrnvnvr4fda
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Yi-Nan Li, Chih-Wei Chen, Thuong Trinh-Minh, Honglin Zhu, Alexandru-Emil Matei, Andrea-Hermina Györfi, Frederic Kuwert, Philipp Hubel, Xiao Ding, Cuong Tran Manh, Xiaohan Xu, Christoph Liebel, Vladyslav Fedorchenko, Ruifang Liang, Jens Pfannstiel, Min-Chuan Huang, Neng-Yu Lin, Andreas Ramming, Georg Schett, Jörg H.W. Distler. "Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153." Zenodo (2022)