Erk调控Wnt通路影响间充质干细胞分化的机制及其在骨质疏松中的作用研究

The osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) play an important role in osteoporosis. Erk signaling pathway regulates the osteogenic and adipogenic differentiation of MSCs. Previous study showed that Erk signaling was activated in MSCs derived from osteoporosis patients. However, the detailed mechanism of Erk signaling regulating MSCs differentiation in osteoporosis is still unknown. In previous study, we crossed floxed erk2 mice with Osx1 (SP7)-GFP::Cre mice to generate MSC/osteoprogenitor-specific conditional erk2 knockout mice (erk2Sp7-/-). Bone volume was increased and the fat tissue in bone marrow was decreased in erk2Sp7-/- mice compared to the control erk2f/f littermate and erk1 knockout (erk1-/-) mice. Furthermore, we screened signaling pathways by cDNA microarray analysis and found that Wnt/β-catenin signaling was significantly elevated in erk2-/- BMMSCs compared to erk2f/f and erk1-/- BMMSCs. Thus, we hypothesized that Erk2, but not Erk1, regulates the the osteogenic and adipogenic differentiation of MSCs through Wnt/β-catenin signaling and Erk2 plays critical role in osteoporosis. We will use erk2Sp7-/- and erk1-/- mice to prove our hypothesis and explore the detailed mechanism of Erk2 regulating Wnt/β-catenin signaling. In addition, we will use Erk2 inhibitor to treat ovariectomized mice to ascertain if inhibition of Erk2 could cure osteoporosis. This study will firstly explore the mechanism of Erk regulating MSCs differentiation in osteoporosis and provide a new approach for osteoporosis treatment.

间充质干细胞（MSC）成骨成脂分化在骨质疏松发病中发挥重要作用，Erk调控MSC成骨成脂分化，且骨质疏松患者MSC的Erk信号通路被激活，但其在骨质疏松中的作用机制仍不清楚。本课题组前期研究构建成骨前体细胞条件性敲除Erk2Sp7-/-小鼠，发现其与正常及Erk1-/-小鼠相比骨质增多且骨髓腔中脂肪组织减少，基因芯片分析发现Erk2-/-与正常及Erk1-/- MSC相比Wnt通路被激活，因此我们推测Erk2而非Erk1通过调节Wnt通路影响MSC的成骨成脂分化。本课题拟以Erk2Sp7-/-及Erk1-/-基因敲除小鼠为模型，明确Erk2而非Erk1调节MSC的成骨成脂分化，Erk2调控Wnt通路影响MSC分化的分子机制，并借助去势小鼠模拟骨质疏松探索抑制Erk2是否能逆转骨质缺失。本课题首次探讨Erk调控MSC分化在骨质疏松发病中的作用机制，并为以Erk为靶点的骨质疏松治疗提供新的思路

骨质疏松（osteoporosis）是一种发病率和危害性都非常高的衰老性疾病，主要表现为骨组织结构受损、骨小梁数量减少、骨质变薄、伴随骨折危险度升高（发生率大于 70%）。目前针对骨质疏松中破骨增强的治疗方案仅能减缓骨质流失的速度，不能有效逆转骨密度减少的事实，并不能从根本上解决骨质缺失的问题，因此探索增加骨密度的方法是骨质疏松治疗的关键。以往研究发现间充质干细胞（MSC）成骨成脂分化在骨质疏松发病中发挥重要作用，Erk调控MSC成骨成脂分化，且骨质疏松患者MSC的Erk信号通路被激活，但其在骨质疏松中的作用机制仍不清楚。.本课题组前期研究构建成骨前体细胞条件性敲除Erk2Sp7-/-小鼠，发现其与正常及Erk1-/-小鼠相比骨质增多且骨髓腔中脂肪组织减少，基因芯片分析发现Erk2-/-与正常及Erk1-/- MSC相比Wnt通路被激活，因此我们推测Erk2而非Erk1通过调节Wnt通路影响MSC的成骨成脂分化。本课题以Erk2Sp7-/-及Erk1-/-基因敲除小鼠为模型，利用Erk1 -/- 及Erk2 Sp7-/- 模型小鼠验证Erk信号通路中是Erk2亚型在间充质干细胞成骨成脂分化中发挥重要的调控作用，进一步分析其机制发现Wnt通路介导Erk2对MSCs成骨成脂分化的调控作用，其中 Ekr2通过Nanog/DNMT1/DKK1调节Wnt/β-catenin信号通路。最后借助去势小鼠模拟骨质疏松明确抑制Erk2能够逆转小鼠骨质缺失，发挥治疗骨质疏松的作用。本课题首次探讨Erk调控MSC分化在骨质疏松发病中的作用机制，并为以Erk为靶点的骨质疏松治疗提供新的思路。