Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway
Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway
复制标题
Exendin-4 通过 PKA-STAT3 信号通路通过骨髓源性巨噬细胞极化诱导骨髓基质细胞迁移
DOI：
10.1159/000485776
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发表时间：
2017-01-01
影响因子：
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通讯作者：
Luo, Xiaoxing
中科院分区：
文献类型：
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作者：
Wang, Ning;Gao, Jian;Luo, Xiaoxing
背景/目的：骨重塑过程中的合成和降解过程受到成骨细胞和破骨细胞的关键调控。GLP-1受体激动剂Exendin-4有利于成骨细胞分化，增加成骨细胞数量。方法：构建去卵巢模型，评价Exendin-4对骨质疏松症骨形成的影响。我们还建立了巨噬细胞缺失模型来研究巨噬细胞对骨形成的影响。将32只3月龄雌性WT C57BL/6小鼠随机分为正常对照组和去卵巢（OVX）亚组：OVX +载药组、OVX + Exendin-4（4.2µg/kg/day）组、OVX +氯磷酸脂质体组和OVX +氯磷酸脂质体+ Exendin-4组。结果：本研究发现Exendin-4不仅能增加成骨细胞数量，减少破骨细胞数量，还能增加骨表面的骨髓基质细胞（BMSCs）数量。此外，我们发现，与OVX小鼠相比，Exendin-4处理的OVX小鼠骨表面TGF-β1水平升高。Exendin-4促进骨髓源性巨噬细胞向M2亚型分化，增加M2亚型TGF-β1的分泌。最后，我们发现Exendin-4通过cAMP-PKA-STAT3信号通路诱导巨噬细胞极化。结论：Exendin-4通过PKA-STAT3信号通路促进骨髓源性巨噬细胞向M2亚型极化，诱导骨髓间质干细胞向骨表面迁移。
Background/Aims: The synthesis and degradation processes involved in bone remodeling are critically regulated by osteoblasts and osteoclasts. The GLP-1 receptor agonist Exendin-4 is beneficial for osteoblast differentiation and increases the number of osteoblasts. Methods: We constructed an ovariectomized model to evaluate the impact of Exendin-4 on bone formation in osteoporosis. A macrophage-depleted model was also created to investigate the effect of macrophages on bone formation. Thirty-two female WT C57BL/6 mice (aged 3 months) were randomly assigned to a normal control group and four ovariectomized (OVX) subgroups: OVX + vehicle group, OVX + Exendin-4 (4.2 µg/kg/day) group, OVX + chloride phosphate liposome group and OVX + chloride phosphate liposome + Exendin-4 group. Results: In this study, we found that Exendin-4 not only increased the number of osteoblasts and decreased the number of osteoclasts, but also increased the number of bone marrow stromal cells (BMSCs) at the bone surface. Moreover, we found that OVX mice treated with Exendin-4 increased TGF-β1 levels at the bone surface compared with that in OVX mice. Besides, Exendin-4 promoted the polarization of bone marrow-derived macrophages into M2 subtype and increased TGF-β1 secretion by the M2 subtype. Finally, we found that Exendin-4 induced macrophage polarization via the cAMP-PKA-STAT3 signaling pathway. Conclusion: Exendin-4 promotes bone marrow-derived macrophage polarization to the M2 subtype and induces BMSC migration to the bone surface via PKA-STAT3 signaling.