Impaired Efferocytosis Enables Apoptotic Osteoblasts to Escape Osteoimmune Surveillance During Aging

作者：Rongyao Xu, Hanyu Xie, Xin Shen, Jiadong Huang, Hengguo Zhang, Yu Fu, Ping Zhang, Songsong Guo, Dongmiao Wang, Sheng Li, Kai Bo Zheng, Wen Sheng Sun, Laikui Liu, Jie Cheng, Hongbing Jiang · 发表于：Advanced Science · 年份：2023 · DOI：10.1002/advs.202303946 · 被引用次数：32 · 研究领域：Phagocytosis and Immune Regulation、Erythrocyte Function and Pathophysiology、Immune cells in cancer

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-SIRPα 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.