MAPK/β-catenin正反馈通路在GLP-1RA调控BMSC分化及改善骨质疏松中的机制研究

The imbalance of bone marrow stromal cell (BMSC) differentiation between osteogenesis and adipogenesis is an important basis for the development of osteoporosis, but there are no drugs targeting the above process. We previously proved that Glucagon-like peptide-1 receptor agonist (GLP-1RA) could promote osteogenesis and inhibit adipogenesis in BMSC in vitro,up-regulating MAPK and β-catenin (β-cat) pathway,while could ameliorate the osteoporosis in ovariectomized (OVX) rats in vivo.MAPK and β-cat pathway appear to be of particular importantce,since activation of both pathway could promote BMSC differentiation into osteoblast cells while suppressing their adipogenic potential. Studies have shown that MAPK could up-regulate β-cat by inhibiting GSK-3β, and β-cat could also increase MAPK. Therefore, we hypothesized that positive feedback pathway between MAPK and β-cat may mediate GLP-1RA regulation of BMSC differentiation. This project intends to carry out the following work: to analysis correlation of GLP-1 and osteoporosis in human body; to determine whether GLP-1RA regulates differentiation of BMSC in OVX rats and ameliorate osteoporosis; to explore the molecular mechanism of GLP-1RA regulation of BMSC differentiation.The confirmation of the above issue will provide theoretical basis for exploring new therapeutic targets of osteoporosis.

骨髓基质干细胞（BMSC）成骨和成脂间分化失衡是骨质疏松重要发病机制，但尚无以此为靶标的治疗药。我们前期发现胰高血糖素样肽-1受体激动剂（GLP-1RA）体外促进BMSC成骨抑制成脂，且激活细胞中MAPK和β-catenin（β-cat）通路；体内改善卵巢切除（OVX）大鼠骨质疏松。已知MAPK和β-cat通路激活有促成骨抑成脂效应，同时研究提示MAPK可通过抑制GSK-3β上调β-cat；β-cat可反馈上调MAPK，故我们推测MAPK/β-cat之间可能存在的正反馈通路介导了GLP-1RA调控BMSC分化的作用。本项目拟开展以下工作：分析人体内GLP-1与骨质疏松相关性；明确GLP-1RA是否通过调控OVX大鼠体内BMSC分化改善骨质疏松；探索GLP-1RA调控BMSC分化的分子机制。本课题分别在人群、动物和细胞层面上阐释GLP-1RA的骨保护作用，为骨质疏松治疗提供了新策略和新靶点。

骨质疏松症是高患病率、高致残致死率的常见慢性代谢性骨病，为国家带来了沉重的医疗负担。同时骨质疏松症患者多合并糖尿病、脂肪肝等慢性代谢性疾病，造成疾病间的互相加强，加重患者病情恶化。现有的骨质疏松药物多以抑制骨吸收为作用靶点，尚无有效药物通过调控骨髓基质干细胞（BMSC）成骨和成脂间分化失衡来治疗骨质疏松。我们的研究发现胰高血糖素样肽-1受体激动（GLP-1RA）体外促进BMSC成骨抑制成脂，且激活细胞中MAPK和β-catenin（β-cat）通路；通过动物实验，我们发现GLP-1RA在体内可显著改善卵巢切除（OVX）大鼠骨质疏松状态。本课题研究期间同时在人群中发现骨细胞因子RANKL是非酒精性脂肪肝(NALFD)独立的危险因素。上述研究提示GLP-1RA是潜在的可同时兼顾骨质疏松和糖尿病治疗的药物；同时研究结果同样提示骨骼作为内分泌器官深度参与了能量代谢，作为骨质疏松症的一种标志物，骨细胞因子RANKL与非酒精性脂肪肝的患病风险增加显著正相关。以上结果不仅为治疗骨质疏松症的药物靶点提供了新的视角，同时也为骨参与能量代谢的机制提供了理论基础。