An incrementally greater understanding of the complex mechanisms driving any given age-related dysfunction will usually offer new approaches to intervention. Even if those approaches do not address root causes, sometimes preventing only the proximate causes can still meaningfully improve outcomes. In today's open access paper, researchers outline specific age-related changes in macrophage behavior that lead to greater cellular senescence in the stem cell and progenitor cell populations important to repair of damaged bone. That greater burden of cellular senescence impairs regeneration following bone injury.
This is one of many examples one might choose to use in order to illustrate the complexity of the relationship between the immune system and other cells in tissues, particularly in the context of regeneration. Innate immune cells such as macrophages clearly play an important role in tissue maintenance and regeneration from injury, as do transient senescent cells. Equally clearly, these cell populations undergo significant changes with age, including greater inflammatory behavior and too many lingering senescent cells. Absent a very specific understanding of the way in which these changes negatively impact other cell populations, it is hard to proceed towards selective interventions, however. One must fall back to senolytic therapies to clear the senescent cells that are known to be a problem without a full understanding of how those cells became senescent.
Osteoporosis is characterized by low bone mass and destroyed microarchitecture, resulting in an increased risk of fracture. Additionally, decreased bone regenerative potential and a high risk of impaired or incomplete fracture healing in elderly individuals contribute to long-term disability or even death. However, the etiology of age-related impaired skeletal regenerative capacity remains incompletely understood.
Aged-related skeletal deterioration and impaired fracture healing are related to the accumulation of senescent cells, which are characterized by permanent cell cycle arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). Our previous study found that senescent immune cells accumulated in the bone marrow and secreted grancalcin (GCA), which suppressed bone turnover and promoted marrow fat accumulation. Thus, accumulated senescent cells in the bone microenvironment play a significant role in skeletal aging, and eliminating senescent cells and/or blunting their SASP factors can prevent or delay age-related bone loss. Recent studies also suggested that the accumulation of senescent cells impaired fracture healing, and removing senescent cells by genetic and pharmacological approaches in aged mice improved fracture repair. However, the effects and underlying mechanisms of senescent cells in fracture healing during aging remain elusive.
In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers skeletal stem cell and progenitor cell (SSPC) senescence and impairs fracture healing. Local injection of human recombinant GCA 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 incomplete fracture healing in elderly individuals.