Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion  

作　　者：Se Hwan Mun Seyeon Bae Steven Zeng Brian Oh Carmen Chai Matthew Jundong Kim Haemin Kim George Kalliolias Chitra Lekha Dahia Younseo Oh Tae-Hwan Kim Jong Dae Ji Kyung-Hyun Park-Min 

机构地区：[1]Arthritis and Tissue Degeneration Program,David Z.Rosensweig Genomics Research Center,New York,NY,USA [2]Tissue Engineering,Regeneration and Repair,Hospital for Special Surgery,New York,NY,USA [3]Department of Cell and Developmental Biology,Weill Cornell Medical College,New York,NY,USA [4]BCMB allied program,Weill Cornell Graduate School of Medical Sciences,New York,NY,USA [5]Hanyang University Institute for Rheumatology Research,Seoul,Korea [6]Department of Rheumatology,Hanyang University Hospital for Rheumatic Diseases,Seoul,Korea [7]Rheumatology,College of Medicine,Korea University,Seoul,Korea [8]Department of Medicine,Weill Cornell Medical College,New York,NY,USA

出　　处：《Bone Research》2021年第4期571-581,共11页骨研究（英文版）

基　　金：This work was supported by the National institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS)of the NIH under Award Numbers R01 AR069562 and AR073156(to K.H.P.-M.).

摘　　要：Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,the role of M-CSF in arthritic bone erosion is not completely understood.Here,we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS,a receptor for M-CSF,leading to the generation of FMS intracellular domain(FICD)fragments.Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses.Moreover,myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model.The FICD formed a complex with DAP5,and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATcl protein expression.Moreover,targeting the MNK1/2 pathway diminished arthritic bone erosion.These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.

关 键 词：OSTEOCLAST stimulating 1/2 

分 类 号：R593.22[医药卫生—内科学]