Impaired Efferocytosis Enables Apoptotic Osteoblasts to Escape Osteoimmune Surveillance During Aging

Macrophage efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis. However, apoOBs frequently accumulate in aged bone marrow, where they may mount proinflammatory responses and progressive bone loss. The reason why apoOBs are not cleared during aging remains unclear. In this study, it is demonstrated that aged apoOBs upregulate the immune checkpoint molecule CD47, which is controlled by SIRT6-regulated transcriptional pausing, to evade clearance by macrophages. Using osteoblast- and myeloid-specific gene knockout mice, SIRT6 is further revealed to be a critical modulator for apoOBs clearance via targeting CD47-SIRP alpha checkpoint. Moreover, apoOBs activate SIRT6-mediated chemotaxis to recruit macrophages by releasing apoptotic vesicles. Two targeting delivery strategies are developed to enhance SIRT6 activity, resulting in rejuvenated apoOBs clearance and delayed age-related bone loss. Collectively, the findings reveal a previously unknown linkage between immune surveillance and bone homeostasis and targeting the SIRT6-regulated mechanism can be a promising therapeutic strategy for age-related bone diseases. Aging-induced immunosenescence is characterized as impaired immune surveillance, contributing to many age-related diseases. However, there is little investigation about how immune surveillance regulates bone homeostasis during aging. Here, for the first time, a new concept of osteoimmune surveillance is put forward and link it to impaired macrophage efferocytosis of apoptotic osteoblasts due to dysfunctional CD47-SIRP alpha checkpoint.image