FoxO1-Runx2通路在正畸应力调控骨质疏松骨改建平衡中的作用及其机制

The requirement of orthodontics treatment for the middle-aged is increasing obviously with the improvement of quality of life, however, a large number of patients have the problem of osteoporosis. Tooth mobility and weakened bone formation ensue with the movement of teeth under the condition of osteoporosis. The mechanism of bone remodelling in teeth movement with osteoporosis becomes the new focus researched in orthodontic. The previous works in animal model and cell model has proven a special phenomenon that BMSCs had capacities for slow proliferation, strong adipogenic differentiation and low osteogenesis, Runx2 played a key role in mechano-transduction pathway of osteogenic differentiation. That regulatory mechanism still remains unknown. We have screened. According to reported studies and our works, we hypothesize: FoxO1, acting upstream of Runx2 induction, may play a pivotal role in regulating the balance of bone remodelling of osteoporosis influenced by stress and probably act through promotion of osteoblast differentiation, The present objectives is planning to decrease and increase the functions of FoxO1 by the RNA interference and gene cloning, investigate the biologic behaviour of BMSCs. It could be a new breakthrough that exploring the roles of FoxO1 in bone remodelling of osteoporosis from cell proliferation and apoptosis, stem cell differentiation and the balance between osteoblasts and osteoclasts can improve the bone remodelling and the shortage of bone formation for the middle-aged by virtue of regulating the FoxO1 gene.

力学信号怎样启动骨质疏松骨细胞内的生物信号，启动骨改建是正畸牙移动、牙列修复重建、和生物力学的交叉研究热点。我们的前期研究表明：骨质疏松状态下骨髓间充质干细胞（BMSC）生长增殖缓慢且在应力刺激下成骨能力减弱、成脂能力增强，Runx2在其中起关键作用，但其上游调控机制不明。借助蛋白芯片及生物信息学手段，我们观察到转录因子FoxO1可以与Runx2的启动子直接结合。因此，我们提出假设：FoxO1可能通过在转录水平调控Runx2的表达，从而促进成骨向分化。本项目拟通过染色质免疫共沉淀及荧光素酶报告系统，鉴定FoxO1与Runx2的直接结合；通过RNA干扰或基因过表达，研究应力刺激下BMSC骨向分化的生物学行为，这一研究将为今后通过调控FoxO1-Runx2通路促进局部骨改建，防治中老年治疗中的牙槽骨成骨不足开拓新思路。

随着社会发展和步入老龄化，越来越多的中老年人开始寻求正畸治疗，骨质疏松状态下能否进行正畸治疗受到越来越多地关注，这一特殊状态下牙移动骨改建机理的研究尤为重要。本课题组前期已成功建立大鼠骨质疏松模型（OVX）和体外培养骨质疏松大鼠骨髓基质干细胞(OVX BMSCs)，围绕Runx2对其改建机理进行了一系列的研究。在这些基础上，本研究以FoxO1为新的切入点。结果发现：①.明确FoxO1参与体外持续牵张应力促进OVX BMSCs成骨向分化这一过程；②.免疫荧光证实与Runx2有一定的协同相互作用；③成功构建靶向FoxO1的RNAi载体，为进一步明确与Runx2相互作用奠定基础；④.明确上游AKT通路可被力学信号激活，可能通过FoxO1这个点在促骨向分化中发挥正向调控作用。目前尚无力学刺激下关于FoxO1参与骨质疏松调控成骨向分化的研究。FoxO1是近些年出现的与骨代谢密切相关的转录因子，在成骨分化中的研究地位越来越重要。本研究初步揭示了FoxO1在应力诱导的骨质疏松骨髓基质干细胞骨向分化中的的重要作用，为进一步深入研究在力学作用与Runx2的相互作用提供了良好的实验基础，为深入阐明骨质疏松状态下牙槽骨的改建机理研究提供了一个新的靶点，展示了良好的研究前景。. 本课题为一年期，目前已完成的考核目标:①.由本基金所资助的直接相关文章已发表6篇（核心期刊），已投稿3篇(1篇核心已录用，1篇SCI收录，1篇核心期刊)。②.国内会议poster 1次。③已培养硕士研究生1名，目前1名硕士和博士研究生正从事课题相关研究。

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