YAP1/RANKL在机械应力诱导破骨细胞分化中的作用及机制

It is a dynamic and complex process that mechanical force induces and regulates alveolar bone remodeling. To fine-tune orthodontic tooth movement and avoid alveolar bone resorption due to excessively high force, the mechanism that how osteoblasts sense mechanical force to promote osteoclasts formation must be figured out. As an important sensor of mechanical signal, YAP1 (Yes-associatedprotein 1) transcription activation factor can convert physical stimuli into chemical signals. Considering the intimate relationship between stress and alveolar bone resorption, we hypothesize that, YAP1 can regulate the differentiation of osteoclasts directly and indirectly as well as the following tooth movementand alveolar bone remodeling by inducing the expression of RANKL and SOX9. To verify this hypothesis, enhanced or reduced YAP1 functions driven by different promoters are developed in vitro, and then the chromatin immunoprecipitation assay is used to investigate the mechanism of YAP1’s effect on the osteoclast differentiation. Finally, through a dog model with teeth intrusion, the osteoclast differentiation and alveolar bone resorption are observed in vivo. We expect to seek the genetic link between mechanical force and alveolar bone resorption. This study will provide us theoretical basis to regulate the tooth movement and alveolar bone resorption reasonably.

研究牙槽骨感受机械应力刺激、促进破骨细胞形成的机制，对于调控正畸牙齿移动的速度或者减少过大应力造成的牙槽骨吸收有着重要的意义。YAP1转录共激活因子是细胞感受机械信号的重要效应因子，我们推测YAP1可以通过促进RANKL和SOX9的表达，直接和间接调控破骨细胞的分化形成。为验证这一假设，我们首先通过应力加载和基因调控，检测YAP1与破骨细胞分化的相关性；其次，通过染色质免疫共沉淀验证YAP1与RNAKL和SOX9启动子上TEAD位点的结合，探讨相关机制；最后，通过建立动物模型，在体内检测应力刺激下YAP1对牙槽骨吸收的影响。通过本研究，我们拟寻求应力刺激与牙槽骨吸收的基因纽带，籍此调控正畸牙齿移动的速度、减少过大应力造成的牙槽骨吸收，为解决临床问题提供新的思路。

研究牙槽骨感受机械应力刺激、促进破骨细胞形成的机制，对于调控正畸牙齿移动的速度或者减少过大应力造成的牙槽骨吸收有着重要的意义。YAP1转录共激活因子是细胞感受机械信号的重要效应因子，作为Hippo信号通路下游重要的效应器，在细胞增殖、分化、凋亡及组织再生中发挥着重要的作用。本研究旨在通过探索YAP1对于成骨、成牙骨质、成软骨等相关细胞分化及矿化的影响，寻求应力刺激与牙槽骨吸收与改建的基因纽带，籍此调控牙齿的移动和牙槽骨的吸收。首先，我们证实YAP1通过调控ID1促进成骨细胞分化；其次，研究进一步证实YAP1促进成牙骨质细胞分化和矿化；再次，研究表明YAP1抑制了TNF-α诱导的骨吸收介质的表达并参与调控NF-KB通路；最后，我们证实YAP1通过激活经典β-catenin信号通路抑制SOX9表达并负向调控前成软骨细胞软骨向和肥大向分化。本研究依次从成骨，成牙骨质，破骨，成软骨等各个方面研究了YAP1调控其分化及矿化的能力及机制，为后续体内调控提供坚实的基础，为解决临床过大应力造成的牙槽骨吸收问题提供新的思路。