力与炎症因子诱导牙周膜细胞分化途径的比较研究

Comparative study of differentiation pathways of PDLCs induced by mechanical signals and inflammatory factors During orthodontic tooth movement, the application of orthodontic force allows teeth to be moved through the periodontal ligaments (PDL) to the supporting alveolar bone and lead to deposition or resorption of bone, depending on whether the tissues are exposed to a tensile of compressive mechanical stress. Periodontal ligament as an unique anatomical structure can response to mechanical signals independently, and induce bone deposit and bone resorption in local alveolar bone. Orthodontic stress may not induce the loss of bone mass, but inflammatory factors can induce the continuous bone resorption. These phenomenon suggested that the differentiation pathway of PDLCs induced by mechanical signals or inflammatory factors may be different. The strength and characters of mechanical stress may affect the mature of osteoblasts differentiated from PDLCs. In the presence of inflammatory factors the maturity of osteoblasts maybe influenced by complicated autocrine and paracrine regulation., which may finally induce the deposit or resorption of local alveolar bone. Wnt signaling is crucial for osteoblastogensis of mesenchymal stem cells. While inflammatory factors can disrupt the Wnt signaling and inhibit the osteoblastogenesis. Eph and Ephrin are cell surface molceules which mediate forward, as well as reverse, cellular signals. The Eph-Ephrin interaction serves as a bidirectional signaling. More details on the regulation of osteoblastic and osteoclastic differentiation by Eph and Ephrin family members have been discovered recently. In this study we plan to investigate the roles of Wnt molecules and the Eph-Ephrin interaction in osteoblastogenesis of PDLCs induced by mechanical signals and inflammatory factors or both of them.

牙周膜这一独特结构具备独立地应答正畸力刺激，启动牙槽骨成骨和破骨的可能。正畸力引起的牙槽骨改建没有骨量丢失，炎症可导致牙槽骨进行性骨量丢失，提示力信号和炎症因子可能通过不同途径诱导牙周膜中未分化细胞的分化。力值强度和力的性质（基底牵张力，流体剪切力）会影响牙周膜细胞分化,并通过复杂的自分泌和旁分泌调节，与炎症因子的作用产生拮抗或协同效果，导致局部骨改建表现出骨沉积和骨吸收。Wnt信号是成骨细胞分化重要调节通路，炎症因子可阻断干细胞向成骨细胞分化，Wnt通路与力和炎症因子影响牙周膜细胞的分化有密切关系。Ephrin-Eph受体-配体的结合在成骨细胞与破骨细胞之间进行双向信号传导，调节局部骨改建，本研究拟以力信号（基底牵张力，流体剪切力）和炎症因子（IL-1,TNFα）为代表，系统观察Wnt信号在牙周膜细胞向成骨细胞分化过程中对功能蛋白表达，细胞内信号传导，细胞表面Eph受体表达的影响。

牙周膜是感应力刺激的重要结构，正畸力可以引起骨形成和骨吸收，完成骨改建，而炎症因子则引起骨的进行性吸收。力信号和炎症因子是否通过不同的途径诱导牙周膜细胞分化，两种刺激是否存在拮抗和协同作用，目前尚不明确。本研究应用生物实验学的方法，观察不同力值牵张力对牙周膜细胞分化的影响，发现长时间的轻力更有利于成骨转录因子的表达，促进成骨。研究还发现在炎症因子的刺激下，周期性牵张力促成骨作用不明显，力刺激不能改变炎症因子对局部骨改建的调节方向。Eph/ephrin介导的双向信号传导可调控成骨-破骨细胞间的耦联作用，这些蛋白在炎症介导的细胞反应和组织重塑中的作用也需大量实验证实，本研究体外观察炎症刺激下牙周膜细胞Eph蛋白家族的表达，结果发现促进骨形成的EphB4/ephriB2蛋白表达降低而促进骨吸收的EphA2蛋白表达增强。本课题对探讨牙周炎患者正畸治疗机理有重要意义。