cc_byLi, Yi-NanChen, Chih-WeiTrinh-Minh, ThuongZhu, HonglinMatei, Alexandru-EmilGyörfi, Andrea-HerminaKuwert, FredericHubel, PhilippDing, XiaoManh, Cuong TranXu, XiaohanLiebel, ChristophFedorchenko, VladyslavLiang, RuifangHuang, KaiyuePfannstiel, JensHuang, Min-ChuanLin, Neng-YuRamming, AndreasSchett, GeorgDistler, Jörg H. W.2024-12-202024-12-202022https://doi.org/10.1038/s41413-022-00218-9https://hohpublica.uni-hohenheim.de/handle/123456789/16946Bone 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.engMedical and Health Sciences610Article18125272842024-12-02