凋亡软骨细胞通过MSR1调控巨噬细胞脂肪酸氧化促进骨折愈合的分子机制研究

骨折不愈合一直是威胁人类健康的主要公共医疗问题，研究普遍认为：软骨内成骨是骨折如期愈合的关键。然而，在该过程中，凋亡软骨细胞对巨噬细胞的功能调节及机制尚不清楚。申请人前期通过非靶向代谢组学发现凋亡软骨细胞可释放大量的长链脂肪酸。组织学及功能学实验进一步表明：巨噬细胞的MSR1对于骨折愈合至关重要，分布于软骨内成骨的移形区巨噬细胞，可通过MSR1摄取、利用游离长链脂肪酸，通过上调脂肪酸氧化，发挥促软骨内成骨的作用。本研究拟在前期基础上，进一步明确:1)经凋亡软骨细胞上清刺激后，巨噬细胞的MSR1上调脂肪酸氧化的具体分子机制；2)利用MSR1基因敲除小鼠结合骨髓移植等实验，探讨靶向巨噬细胞的MSR1及其调控的关键分子促进骨愈合的效果，为临床治疗骨折不愈合或延期愈合提供全新的策略及有效的靶点。

Fracture nonunion has always been a major public medical problem threatening human health. It is known that endochondral ossification is the key path of fracture healing. However, the regulatory role and mechanism of apoptotic chondrocytes on macrophages are not well defined. Previously, through untargeted metabolomics, we found apoptotic chondrocytes can release large amounts of long chain fatty acids. Histological and functional results showed that macrophage MSR1 is essential for fracture healing. They are distributed in chondro-osseous transition zone and could promote endochondral osteogenesis via facilitating fatty acid oxidation (FAO). Based on previous results, we aim to: 1) elucidate the molecular mechanism by which macrophage MSR1 regulates FAO; 2) verify the effect of macrophage MSR1 and its regulated molecules on fracture repair using MSR1 knockout mice and bone marrow transplantation experiment. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.