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

Li YN, Chen CW, Trinh MT, Zhu H, Matei AE, Györfi AH, Kuwert F, Hubel P, Ding X, TRAN MANH C, Xu X, Liebel C, Fedorchenko V, Liang R, Huang K, Pfannstiel J, Huang MC, Lin NY, Ramming A, Schett G, Distler J (2022)


Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 10

Article Number: 51

Journal Issue: 1

DOI: 10.1038/s41413-022-00218-9

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.

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APA:

Li, Y.-N., Chen, C.-W., Trinh, M.T., Zhu, H., Matei, A.-E., Györfi, A.-H.,... Distler, J. (2022). Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153. Bone Research, 10(1). https://doi.org/10.1038/s41413-022-00218-9

MLA:

Li, Yi-Nan, et al. "Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153." Bone Research 10.1 (2022).

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