机械敏感钙离子通道蛋白Piezo1在咬合应力调控成骨改建防止骨质疏松牙槽骨骨丢失中的作用及机制研究

Alveolar bone is the foundation of oral function. Our previous study confirmed that estrogen deficiency could induce alveolar bone loss and osteoporosis. Prevention of alveolar bone loss under osteoporosis is critical for oral function and treatment. With an occlusal stress loss model， we found occlusal stress play an important role in prevention of alveolar bone loss via promoting bone formation remodeling in OVX rats. However, it is still unclear that the mechanism by which alveolar bone feels and transducts the occlusal stress. Piezo1 is a type of mechanosensitive ion channel protein whose protein structure has been described in 2018. With a bone mesenchymal stem cells (BMSCs) specific Piezo1 knockout mice model with prx1-Cre, we found Piezo1 can promote bone formation remodeling and is quite sensitive to the stress. We hypothesized that the occlusal stress may promote the osteogenic differentiation of BMSCs by activating Piezo1, thus playing an important part in enhancing the bone remodeling to prevent bone alveolar loss under osteoporosis. Based on the previous experiments, this project intend to construct conditional knockout animal model, utilize the technique of immune coprecipitation and activating or blocking downstream pathway, verify in vivo, to systematically explore the role of Piezo1 in occlusal stress-induced alveolar bone formation remodeling. It will not only be helpful to obtain a new understanding of biomechanical regulation of osteoporotic alveolar bone remodeling, but also meaningful to find a new target to prevent bone loss and develop fresh insights of mechanical biology.

牙槽骨是口腔功能的基础，我们已证实牙槽骨会发生骨质疏松，防止骨质疏松牙槽骨骨量丢失的学科意义重大。前期建立咬合应力丧失模型，发现咬合应力通过促进成骨改建在防止骨丢失中发挥关键作用。牙槽骨是如何感受咬合应力并转化为生物信号，机制不明。机械敏感钙离子通道蛋白Piezo1是最新解析的力敏感离子通道蛋白，课题组前期选用Prx1-Cre构建BMSCs特异Piezo1敲除小鼠，发现其可促进成骨改建且对应力敏感。经过初步验证，提出假设：咬合应力可能通过激活Piezo1促进BMSCs成骨向分化，从而在增强成骨改建防止骨质疏松牙槽骨骨丢失中发挥重要作用。本项目拟在前期基础上，构建诱导型条件敲除模型，利用免疫共沉淀、激活或阻断下游通路等技术，并进行体内验证，系统研究Piezo1在咬合应力调控牙槽骨成骨改建中的机制，既为力学调控骨质疏松牙槽骨改建机理提出新认识，又为发现新靶点防止骨丢失，开拓新的力学生物学思路。

健康的牙槽骨是口腔功能和口腔治疗的基石。在老龄化人口中，越来越多需要口腔治疗的绝经后妇女因雌激素缺乏而出现牙槽骨丢失。局部因素（咬合力丧失）和全身因素（雌激素缺乏）都会影响他们的牙槽骨健康，但其中的关联仍有待阐明。本项目发现咬合力对于维持牙槽骨质量至关重要，而 PIEZO1 协调机械力和雌激素，从而调控牙槽骨稳态。从机制上讲，咬合力损失和 PIEZO1 缺失都可能损害牙槽骨的成骨改建，并通过 Fas 配体 (FasL) 诱导的破骨细胞凋亡进而调节骨吸收。 PIEZO1 可能促进雌激素受体 1 (ESR1) 的活性，后者协同调节 FasL 的转录。本项目揭示了咬合力和雌激素的协同作用，通过 PIEZO1-ESR1-FasL 通路维持牙槽骨稳态。我们的工作支持早期通过牙科治疗恢复咬合力，并提出建议——预防牙槽骨丢失是口腔治疗首要任务。 PIEZO1 不仅可以作为咬合力损失引起的牙槽骨丢失的治疗靶点，还可以作为老年患者代谢性骨丢失的潜在治疗靶点。