胰高血糖素样肽-1受体介导骨髓巨噬细胞极化调控骨重建功能及分子机制研究

项目名称： 胰高血糖素样肽-1受体介导骨髓巨噬细胞极化调控骨重建功能及分子机制研究

项目编号： No.81471093

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 孟静茹

作者单位： 中国人民解放军第四军医大学

项目金额： 75万元

中文摘要： 骨质疏松(OP)是严重危害人类健康的全球公共卫生问题，其发病机制及防治研究是当前热点。我们前期发现GLP-1受体激动剂能有效治疗OP，但机制不清。骨髓微环境中IL-1、IL-6、TNF-α是维持骨重建平衡的重要细胞因子，巨噬细胞极化是其主要来源之一。文献和我们前期研究表明OP大鼠IL-1等分泌增多，巨噬细胞向M1极化；而GLP-1受体激动剂能有效治疗OP，降低IL-1等表达，抑制巨噬细胞的M1极化。成骨和破骨细胞上均不存在GLP-1受体，但巨噬细胞膜表面表达GLP-1受体，因此我们提出假说：GLP-1通过激活其受体调控骨髓巨噬细胞极化，改善骨重建平衡，治疗骨质疏松。本课题拟在多水平、多层次证实GLP-1调控骨髓巨噬细胞极化、治疗骨质疏松的作用及其机制。旨在揭示OP发病新机制，完善骨重建平衡的分子调控网络；阐明GLP-1受体调控骨代谢、改善骨重建平衡的分子机制，为防治OP提供新靶标和新药物。

中文关键词： 骨质疏松；胰高血糖素样肽-1受体；巨噬细胞；极化

英文摘要： Osteoporosis (OP) is a growing public problem currently seriously affecting more than 200 million people's health worldwide. Currently, studying the pathogenesis of osteoporosis and developing new therapy have attracted more attentions. We previously found GLP-1 agonist exendin-4 could effectively treat osteoporosis. So far the mechanism is almost entirely unclear. Inflammatory cytokines in bone marrow microenvironment, including IL-1、IL-6 and TNF-α, are important for keeping bone remodeling balance. Many cells, such as macrophages, can produce inflammatory cytokines. The results of our previous study and reference showed the production and expression of IL-1, IL-6 and TNF-α were significantly increased in serum and bone tissue of osteoporotic rats. Meanwhile M1 macrophage-specific molecule MCP-1 was increased and M2 macrophage-specific molecule Arg-1 was reduced, indicating M1 polarization of macrophages was enhanced in osteoporosis. Exendin-4 could effectively ameliorate osteoporotic symptoms and decrease the production and expressions of IL-1, IL-6, TNF-α, MCP-1 and increased the level of Arg-1 in osteoporotic rats. As the same time, GLP-1 receptor is expressed on macrophages but not on osteoblasts and osteoclasts. So in this project we hypothesize that GLP-1 could improve bone remodeling balance and treat osteoporosis by regulating bone marrow macrophage polarization via activating GLP-1 receptor expressed on macrophages. In our research, we plan to investigate the correlation between bone marrow macrophage polarization and osteoporosis, and then to explore the protective effects and molecular machanisms of GLP-1 on osteoporosis through regulation of macrophage polarization. This study will reveal the new pathogenesis of osteoporosis, elucidate the molecular mechanism of GLP-1 regulating bone metabolism and bone remodeling, as well as explore new target and new drug for osteoporosis treatment.

英文关键词： osteoporosis;GLP-1 receptor;macrophage;polarization