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.

骨骼干/祖细胞（SSPC）衰老是骨再生潜力随年龄下降的主要原因，但 SSPC 衰老的原因仍不清楚。在这项研究中，我们发现老茧中的巨噬细胞在衰老过程中会分泌包括小粒钙素（GCA）在内的衰老因子，从而引发 SSPC 衰老并损害骨折愈合。在年轻小鼠中局部注射人 rGCA 可诱导 SSPC 衰老并延迟骨折修复。单核细胞/巨噬细胞中Gca的基因缺失足以恢复衰老小鼠的骨折修复并缓解 SSPC 衰老。从机制上讲，GCA 与 plexin-B2 受体结合并激活 Arg2 介导的线粒体功能障碍，导致细胞衰老。SSPC 中Plxnb2的耗尽会损害骨折愈合。GCA 中和抗体的施用可增强老年小鼠的骨折愈合。因此，我们的研究表明，愈伤组织内的衰老巨噬细胞会分泌 GCA 来引发 SSPC 继发性衰老，而 GCA 中和代表了治疗老年人骨不连或延迟愈合的一种有前景的疗法。