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.

骨骼干细胞/祖细胞 （SSPC） 衰老是随着衰老而导致骨再生潜力降低的主要原因，但 SSPC 衰老的原因尚不清楚。在这项研究中，我们揭示了愈伤组织中的巨噬细胞在衰老过程中分泌前色素，包括广钙素 （GCA），这会触发 SSPC 衰老并损害骨折愈合。年轻小鼠局部注射人 rGCA 诱导 SSPC 衰老和骨折修复延迟。单核细胞/巨噬细胞中 Gca 的基因缺失足以使老年小鼠的骨折修复恢复活力并减轻 SSPC 衰老。从机制上讲，GCA 与丛蛋白-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。SSPCs 中 Plxnb2 的耗竭会损害骨折愈合。GCA 中和抗体的给药增强了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分泌 GCA 以触发 SSPC 继发衰老，GCA 中和代表了老年人不愈合或延迟愈合的一种有前途的疗法。