桃红四物汤靶向VEGF-FAK信号通路调控骨髓间充质干细胞迁移促进骨折修复的机制研究

The fracture repair failure is increasing. Elucidating the mechanisms and improving the efficiency bone repair is particularly urgent. Our previous studies found that Taohong Siwu Decoction as a basic prescriptioncan effectively promote fracture healing and increase the expression of the vascular endothelial growth factor (VEGF) in the bone callus under the guidance of “Promoting Blood Circulation and Removing Stasis”. The migration of bone marrow mesenchymal stem cells (BMSCs) to fracture site is the key mechanism for fracture healing. Recent studies showed that VEGF can effectively promote the migration of BMSCs in vitro, which is mainly based on activation of focal adhesion kinase (FAK) signaling pathway. Therefore, we hypothesis that Taohong Siwu Decoction may stimulate the secretion of VEGF and maintain its local effective concentration to activate the FAK signaling pathway. Futhermore, VEGF-FAK activation might promote BMSCs migration to the fracture site, and ultimately induce osteogenic differentiation of BMSCs to promote fracture repair. Our research will investigate the molecular mechanism of Taohong Siwu Decoction-mediated VEGF-FAK signaling pathway activation, BMSCs migration and fracture repair in vitro and in vivo. Execution of these studies may provide a new target for Taohong Siwu Decoction in fracture healing, enrich the scientific connotation of "Promoting Blood Circulation and Removing Stasis" theory and provide a new idea or direction in the treatment of fracture in TCM.

骨折修复失败的风险不断升高，积极研究促进骨损伤修复的机制、寻找提高骨折修复效率的方法尤为重要。前期研究发现“活血祛瘀”方桃红四物汤为中医伤科治疗骨折的基本方，能有效促进骨折愈合并提高和维持骨痂内血管内皮生长因子（VEGF）的水平。骨髓间充质干细胞（BMSCs）能向骨折断端迁移是骨损伤修复的关键机制。最新研究表明VEGF可以促进骨髓间充质干细胞（BMSCs）迁移，且主要通过黏着斑激酶（FAK）信号通路的激活。因此我们推断：桃红四物汤可能通过刺激VEGF的分泌和维持局部有效浓度，激活FAK信号通路引起BMSCs向骨折端迁移，最终诱导BMSCs向成骨分化促进骨折修复。本项目拟从细胞和动物水平干预，研究桃红四物汤靶向VEGF-FAK信号通路介导BMSCs迁移及骨折修复的分子机制，为桃红四物汤促进骨折修复提供新的作用靶点，丰富中医“活血化瘀”理论的科学内涵，为中医药治疗骨折提供全新的的思路和方向。

骨折修复失败的风险不断升高，积极研究促进骨损伤修复的机制、寻找提高骨折修复效率的方法尤为重要。前期研究发现“活血祛瘀”方桃红四物汤为中医伤科治疗骨折的基本方，能有效促进骨折愈合并提高和维持骨痂内血管内皮生长因子（VEGF）的水平。骨髓间充质干细胞（BMSCs）向骨折断端归巢是骨损伤修复的关键机制。本项目拟从细胞和动物水平，研究桃红四物汤靶向VEGF/FAK信号通路介导BMSCs归巢及骨折修复的分子机制。研究证实，桃红四物汤早期干预骨折大鼠，能明显增强成骨能力，增加骨痂体积，提高骨矿化密度。研究发现桃红四物汤不仅能促进骨髓内MSCs 动员，增强外周血 BMSCs 迁移能力，增加早期骨痂内 BMSCs归巢数目；同时能促进血管内皮细胞迁移和体外血管形成能力，并增加成骨分化相关标记的表达。其促进骨修复的机制可能与介导VEGF/FAK信号促进BMSCs增殖、迁移和成骨分化及HIF-1α/VEGF信号调控血管生成和成骨分化有关。本研究将为桃红四物汤促进骨折修复提供新的作用靶点，丰富中医“活血化瘀”理论的科学内涵，为中医药治疗骨折提供全新的的思路和方向。