1Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China; 2Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China; 3Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China; 4Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, Hunan 410008, China; 5Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China; 6School of Biomedical Sciences, Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; 7Department of Orthopaedics, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China; 8National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Received
Published Online
2024-07-10
2024-07-10
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Abstract
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.
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