Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3β/β-catenin pathway
Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3β/β-catenin pathway
复制标题
巨噬细胞MSR1通过激活PI3K/AKT/GSK3 beta/beta-catenin通路促进BMSC成骨分化和M2样极化
DOI：
10.7150/thno.36930
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Fan, Jin
中科院分区：
文献类型：
--
作者：
Zhao, Shu-Jie;Kong, Fan-Qi;Fan, Jin
Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications.近年来，巨噬细胞在骨折愈合过程中通过成骨途径调节骨髓干细胞（BMSC）分化的作用备受关注。方法：采用胫骨单皮质缺损模型确定巨噬细胞清道夫受体1（MSR1）在体内膜内骨化（IO）过程中的关键作用。利用 qPCR、Western blotting、免疫荧光和 RNA 测序，在骨髓源性巨噬细胞 (BMDM)、RAW264.7 细胞和 BMSC 的共培养系统中探索 MSR1 的潜在功能和机制。 结果：在本研究中，使用胫骨单皮质缺损模型，我们观察到与 MSR1 野生型 (WT) 小鼠相比，MSR1 敲除 (KO) 小鼠的 IO 延迟。此外，巨噬细胞MSR1介导的PI3K/AKT/GSK3β/β-连环蛋白信号增强了共培养系统中促进BMSC成骨分化的能力。我们还确定了增殖物激活受体γ共激活因子1-α（PGC1α）作为共培养系统中巨噬细胞MSR1激活的PI3K/AKT/GSK3β/β-连环蛋白通路的靶基因，通过增强线粒体氧化磷酸化促进M2样极化。结论：我们的研究结果揭示了MSR1在骨折修复过程中巨噬细胞中以前未被识别的功能。 Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.
Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention.Methods: The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) in vivo. The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing.Results: In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3 beta/beta-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1 alpha) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3 beta/beta-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation.Conclusion: Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.