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

作　　者：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 Kaiyue Huang Jens Pfannstiel Min-Chuan Huang Neng-Yu Lin Andreas Ramming Georg Schett Jörg H.W.Distler 

机构地区：[1]Department of Internal Medicine 3–Rheumatology and Immunology,Friedrich Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen,Erlangen,Germany [2]Deutsches Zentrum für Immuntherapie,Friedrich Alexander University Erlangen-Nuremberg and Universitaetsklinikum Erlangen,Erlangen,Germany [3]Department of Rheumatology,Xiangya Hospital,Central South University,Changsha,Hunan,China [4]Core Facility Hohenheim,University of Hohenheim,Stuttgart,Germany [5]Graduate Institute of Anatomy and Cell biology,National Taiwan University College of Medicine,Taipei,Taiwan

出　　处：《Bone Research》2022年第4期799-815,共17页骨研究（英文版）

基　　金：financial support provided by the following grants and institutions:Grants DI 1537/7-1, DI 1537/8-1, DI 1537/9-1, DI 1537/9-2, DI 1537/11-1,DI 1537/12-1, DI 1537/13-1, DI 1537/14-1, DI 1537/17-1, DI 1537/20-1, DI 1537/22-1,MA 9219/2-1, RA 2506/3-1 and ZH 809/2-1 of the Deutsche Forschungsgemeinschaft(DFG, German Research Foundation);SFB CRC1181 (project C01);SFB TR221/project number 324392634 (B04) and project number 52732026 of the DFG;grants J40, J82,A79 and A64 of the IZKF in Erlangen;grant 2013.056.1 of the Wilhelm-SanderFoundation;grants 2014_A47 and 2014_A184 of the Else-Kr?ner-Fresenius-Foundation;grant 14-12-17-1-Bergmann, 21-07-23-1-Gy?rfi;19-12-06-1-Matei of the ELAN-Foundation Erlangen,MASCARA program/TP2 (01EC1903A) of Federal Ministry of Education and Research (BMBF);China Scholarship Council;research Award of the German Scleroderma Foundation (Deutsche Stiftung Sklerodermie);Edith Busch Stiftung;a Career Support Award of Medicine of the Ernst Jung Foundation;Open Access funding enabled and organized by Projekt DEAL。

摘　　要：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-linkedβ-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.TNFαfosters 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.

关 键 词：OSTEOCLAST HOMEOSTASIS maintained 

分 类 号：R593.22[医药卫生—内科学]