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 differe...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.展开更多
Dear Editor,Tumor microenvironment(TME)-dependent stromal cell plasticity governs tumor development and therapy response.Tumor endothelial cells(TECs)are a major cellular component in this context[1].In colorectal car...Dear Editor,Tumor microenvironment(TME)-dependent stromal cell plasticity governs tumor development and therapy response.Tumor endothelial cells(TECs)are a major cellular component in this context[1].In colorectal carcinoma(CRC),the stromal cell-dependent impact of the TME is illustrated by an improved survival depending on an interferon(IFN)-γ-dominated Th1-like TME associated with high T-cell density[2]and suppressed angiogenesis[3,4].Cellular transcriptional memory is reported in cell lines after repeated exposure to IFN-γin vitro[5],suggesting that a Th1-like TME may also exert stable imprinting effects in vivo.Here,we investigated whether TME-dependent transcriptional imprinting in TECs from CRC patients can be exploited to retrieve clinically relevant signatures predicting outcomes.展开更多
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)+10 种基金SFB TR221/project number 324392634 (B04) and project number 52732026 of the DFGgrants J40, J82,A79 and A64 of the IZKF in Erlangengrant 2013.056.1 of the Wilhelm-SanderFoundationgrants 2014_A47 and 2014_A184 of the Else-Kr?ner-Fresenius-Foundationgrant 14-12-17-1-Bergmann, 21-07-23-1-Gy?rfi19-12-06-1-Matei of the ELAN-Foundation Erlangen,MASCARA program/TP2 (01EC1903A) of Federal Ministry of Education and Research (BMBF)China Scholarship Councilresearch Award of the German Scleroderma Foundation (Deutsche Stiftung Sklerodermie)Edith Busch Stiftunga Career Support Award of Medicine of the Ernst Jung FoundationOpen Access funding enabled and organized by Projekt DEAL。
文摘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.
基金German Research Foundation.Grant Numbers:FOR2438,280163318DFGSFB/TRR241,375876048+2 种基金DFGSTU238/10-1,437201724DFGTRR305,429280966DFG-NOTICE,493624887 Interdisciplinary Center for Clinical Research Programm zur Förderung von Corona-Forschungsprojekten W.Lutz Stiftung Forschungsstiftung Medizin am Universitätsklinikum Erlangen German Federal Ministry of Education and Research.Grant Numbers:01KT1801,031L0262C Chinese scholarship program。
文摘Dear Editor,Tumor microenvironment(TME)-dependent stromal cell plasticity governs tumor development and therapy response.Tumor endothelial cells(TECs)are a major cellular component in this context[1].In colorectal carcinoma(CRC),the stromal cell-dependent impact of the TME is illustrated by an improved survival depending on an interferon(IFN)-γ-dominated Th1-like TME associated with high T-cell density[2]and suppressed angiogenesis[3,4].Cellular transcriptional memory is reported in cell lines after repeated exposure to IFN-γin vitro[5],suggesting that a Th1-like TME may also exert stable imprinting effects in vivo.Here,we investigated whether TME-dependent transcriptional imprinting in TECs from CRC patients can be exploited to retrieve clinically relevant signatures predicting outcomes.
