Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing  

作　　者：Nan-Yu Zou Ran Liu Mei Huang Yu-Rui Jiao Jie Wei Yangzi Jiang Wen-Zhen He Min Huang Yi-Li Xu Ling Liu Yu-Chen Sun Mi Yang Qi Guo Yan Huang Tian Su Ye Xiao Wei-Shan Wang Chao Zeng Guang-Hua Lei Xiang-Hang Luo Chang-Jun Li 

机构地区：[1]Department of Endocrinology,Endocrinology Research Center,Xiangya Hospital of Central South University,Changsha,Hunan 410008,China [2]Department of Orthopaedics,Xiangya Hospital of Central South University,Changsha,Hunan 410008,China [3]Department of Epidemiology and Health Statistics,Xiangya School of Public Health,Central South University,Changsha,China [4]Hunan Key Laboratory of Joint Degeneration and Injury,Changsha,Hunan 410008,China [5]Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment,Ministry of Education,Xiangya Hospital,Central South University,Changsha,China [6]School of Biomedical Sciences,Institute for Tissue Engineering and Regenerative Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong SAR,China [7]Department of Orthopaedics,The First Affiliated Hospital of Shihezi University,Shihezi,Xinjiang,China [8]National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan 410008,China

出　　处：《Bone Research》2024年第1期122-136,共15页骨研究（英文版）

基　　金：This work was supported by the National Key R&D Program of China(Project No.2019YFA0111900 to C.J.L.and Y.J.,2022YFC3601900 to G.H.L.,2022YFC3601903 to X.H.L.,and 2022YFC3601905);the National Natural Science Foundation of China(Grant Nos.82261160397,82272560,81922017 to C.J.L.and 81930022,91749105 to X.H.L.);the NSFC/RGC Joint Research Scheme,the Research Grants Council(UGC)of the Hong Kong Special Administrative Region and the National Natural Science Foundation of China(NSFC/RGC Project No.N_CUHK483/22 to Y.J.);the Hunan Provincial Science and Technology Department(2023JJ30896 to C.J.L.);the Key Research and Development Program of Hunan Province(2022SK2023 to C.J.L.);the Science and Technology Innovation Program of Hunan Province(2023RC1027 to C.J.L.,2022RC1009 to J.W,and 2022RC3075 to C.Z.).

摘　　要：Skeletal stem/progenitor cell(SSPC)senescence is a major cause of decreased bone regenerative potential with aging,but the causes of SSPC senescence remain unclear.In this study,we revealed that macrophages in calluses secrete prosenescent factors,including grancalcin(GCA),during aging,which triggers SSPC senescence and impairs fracture healing.Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair.Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence.Mechanistically,GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction,resulting in cellular senescence.Depletion of Plxnb2 in SSPCs impaired fracture healing.Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice.Thus,our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence,and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

关 键 词：healing UNION SENESCENCE 

分 类 号：R683[医药卫生—骨科学]