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

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
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
{"title":"Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.","authors":"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","doi":"10.1038/s41413-023-00309-1","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":14.3000,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10808101/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bone Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41413-023-00309-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
引用次数: 0

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.

Abstract Image

在骨折愈合过程中,巨噬细胞与年龄相关的颗粒钙素分泌会诱导骨骼干细胞/祖细胞衰老。
骨骼干/祖细胞(SSPC)衰老是随着年龄增长骨再生潜力下降的主要原因,但SSPC衰老的原因仍不清楚。在这项研究中,我们发现胼胝体中的巨噬细胞在衰老过程中会分泌包括粒钙蛋白(GCA)在内的前衰老因子,从而引发SSPC衰老并影响骨折愈合。向幼鼠局部注射人rGCA可诱导SSPC衰老并延迟骨折修复。遗传性删除单核细胞/巨噬细胞中的Gca足以使老龄小鼠的骨折修复恢复活力并缓解SSPC衰老。从机理上讲,GCA 与 plexin-B2 受体结合并激活 Arg2 介导的线粒体功能障碍,从而导致细胞衰老。SSPCs中Plxnb2的消耗会影响骨折愈合。给予 GCA 中和抗体可增强老年小鼠的骨折愈合。因此,我们的研究揭示了胼胝体中的衰老巨噬细胞会分泌 GCA 引发 SSPC 继发性衰老,而 GCA 中和是一种治疗老年人骨折不愈合或延迟愈合的有效方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信