RUFY4 deletion prevents pathological bone loss by blocking endo-lysosomal trafficking of osteoclasts  

作　　者：Minhee Kim Jin Hee Park Miyeon Go Nawon Lee Jeongin Seo Hana Lee Doyong Kim Hyunil Ha Taesoo Kim Myeong Seon Jeong Suree Kim Taesoo Kim Han Sung Kim Dongmin Kang Hyunbo Shim Soo Young Lee 

机构地区：[1]Department of Life Science,Ewha Womans University,Seoul 03760,South Korea [2]The Research Center for Cellular Homeostasis,Ewha Womans University,Seoul 03760,South Korea [3]Department of Biomedical Engineering,Yonsei University,Wonju 26493,South Korea [4]KM Convergence Research Division,Korea Institute of Oriental Medicine,Daejeon 34054,South Korea [5]Chuncheon Center,Korea Basic Science Institute,Chuncheon 24341,South Korea [6]Fluorescence Core Imaging Center and Bioimaging Data Curation Center,Ewha Womans University,Seoul 03760,South Korea [7]Multitasking Macrophage Research Center,Ewha Womans University,Seoul 03760,South Korea

出　　处：《Bone Research》2024年第2期407-420,共14页骨研究（英文版）

基　　金：supported by grants from the National Research Foundation of Korea(RS-2023-00217798 and 2021R1A2C3003675 to S.Y.L.);by the Korea Basic Science Institute National Research Facilities&Equipment Center grant(2019R1A6C1010020).M.K.was supported in part by scholarship from Ewha Womans University.

摘　　要：Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border.However,the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown.Here,we show with GeneChip analysis that RUN and FYVE domain-containing protein 4(RUFY4)is strongly upregulated during osteoclastogenesis.Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo.Furthermore,deleting Rufy4 did not affect osteoclast differentiation,but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes,their trafficking to the membrane,and their secretion of cathepsin K into the extracellular space.Mechanistically,RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes.Consequently,Rufy4-deficient mice were highly protected from lipopolysaccharide-and ovariectomy-induced bone loss.Thus,RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.

关 键 词：OSTEOCLAST inhibited traffic 

分 类 号：R68[医药卫生—骨科学]