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Original Article | Open Access

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

Nan-Yu Zou1, Ran Liu1, Mei Huang1, Yu-Rui Jiao1, Jie Wei2,3,4,5 , Yangzi Jiang6, Wen-Zhen He1, Min Huang1, Yi-Li Xu1, Ling Liu1, Yu-Chen Sun1, Mi Yang1, Qi Guo1, Yan Huang1, Tian Su1, Ye Xiao1 , Wei-Shan Wang7, Chao Zeng2,3,4,5,8, Guang-Hua Lei2,4,5,8 , Xiang-Hang Luo1,5,8( ), Chang-Jun Li1,5,8 ( )
Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
Department 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
School of Biomedical Sciences, Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
Department of Orthopaedics, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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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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Bone Research
Volume 12,
2024
Article number: 6
DOI: 10.1038/s41413-023-00309-1

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Cite this article:
Zou N-Y, Liu R, Huang M, et al. Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing. Bone Research, 2024, 12: 6. https://doi.org/10.1038/s41413-023-00309-1

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Received: 20 July 2023
Revised: 01 December 2023
Accepted: 05 December 2023
Published: 25 January 2024
© The Author(s) 2024

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