Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healingOAMEDLINE
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.
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;
Department of Endocrinology,Endocrinology Research Center,Xiangya Hospital of Central South University,Changsha,Hunan 410008,ChinaDepartment of Orthopaedics,Xiangya Hospital of Central South University,Changsha,Hunan 410008,China Department of Epidemiology and Health Statistics,Xiangya School of Public Health,Central South University,Changsha,China Hunan Key Laboratory of Joint Degeneration and Injury,Changsha,Hunan 410008,China Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment,Ministry of Education,Xiangya Hospital,Central South University,Changsha,ChinaSchool of Biomedical Sciences,Institute for Tissue Engineering and Regenerative Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong SAR,ChinaDepartment of Orthopaedics,The First Affiliated Hospital of Shihezi University,Shihezi,Xinjiang,ChinaDepartment of Orthopaedics,Xiangya Hospital of Central South University,Changsha,Hunan 410008,China Department of Epidemiology and Health Statistics,Xiangya School of Public Health,Central South University,Changsha,China Hunan Key Laboratory of Joint Degeneration and Injury,Changsha,Hunan 410008,China Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment,Ministry of Education,Xiangya Hospital,Central South University,Changsha,China National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan 410008,ChinaDepartment of Orthopaedics,Xiangya Hospital of Central South University,Changsha,Hunan 410008,China Hunan Key Laboratory of Joint Degeneration and Injury,Changsha,Hunan 410008,China Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment,Ministry of Education,Xiangya Hospital,Central South University,Changsha,China National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan 410008,ChinaDepartment of Endocrinology,Endocrinology Research Center,Xiangya Hospital of Central South University,Changsha,Hunan 410008,China Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment,Ministry of Education,Xiangya Hospital,Central South University,Changsha,China National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan 410008,China
临床医学
healingunionsenescence
《Bone Research》 2024 (001)
P.122-136 / 15
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.).
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