Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, 210029, China.
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, 210029, China; Department of Orthopedics, Xishan People's Hospital of Wuxi City, Wuxi, Jiangsu, 21405, China.
Redox Biol. 2022 Jul;53:102326. doi: 10.1016/j.redox.2022.102326. Epub 2022 Apr 30.
The nonunion following a fracture is associated with severe patient morbidity and economic consequences. Currently, accumulating studies are focusing on the importance of macrophages during fracture repair. However, details regarding the process by which macrophages facilitate endochondral ossification (EO) are largely unknown. In this study, we present evidence that apoptotic chondrocytes (ACs) are not inert corpses awaiting removal, but positively modulate the osteoinductive ability of macrophages. In vivo experiments revealed that fatty acid (FA) metabolic processes up-regulated following EO. In vitro studies further uncovered that FAs derived from ACs are taken up by macrophages mainly through macrophage scavenger receptor 1 (MSR1). Then, our functional experiments confirmed that these exogenous FAs subsequently activate peroxisome proliferator-activated receptor α (PPARα), which further facilitates lipid droplets generation and fatty acid oxidation (FAO). Mechanistically, elevated FAO is involved in up-regulating the osteoinductive effect by generating BMP7 and NAD/SIRT1/EZH2 axis epigenetically controls BMP7 expression in macrophages cultured with ACs culture medium. Our findings advanced the concept that ACs could promote bone regeneration by regulating metabolic and function reprogram in macrophages and identified macrophage MSR1 represents a valuable target for fracture treatments.
骨折后不愈合与严重的患者发病率和经济后果相关。目前，越来越多的研究集中在巨噬细胞在骨折修复过程中的重要性。然而，关于巨噬细胞促进软骨内骨化（endochondral ossification，EO）的过程的细节在很大程度上还不清楚。在这项研究中，我们提供了证据表明，凋亡的软骨细胞（apoptotic chondrocytes，ACs）并不是等待清除的惰性尸体，而是积极调节巨噬细胞的成骨诱导能力。体内实验表明，EO 后脂肪酸（fatty acids，FAs）代谢过程上调。体外研究进一步揭示，ACs 来源的 FAs 主要通过巨噬细胞清道夫受体 1（macrophage scavenger receptor 1，MSR1）被巨噬细胞摄取。然后，我们的功能实验证实，这些外源性 FAs 随后激活过氧化物酶体增殖物激活受体 α（peroxisome proliferator-activated receptor α，PPARα），进一步促进脂滴生成和脂肪酸氧化（fatty acid oxidation，FAO）。在机制上，FAO 的增加通过产生 BMP7 和 NAD/SIRT1/EZH2 轴参与调控巨噬细胞中 BMP7 的表达，从而上调成骨诱导作用。我们的发现推进了这样一种概念，即 ACs 通过调节巨噬细胞的代谢和功能重编程来促进骨再生，并确定巨噬细胞 MSR1 是骨折治疗的一个有价值的靶点。
