TNF-α/NF-κB信号通路在正畸牙移动中PDLSCs介导的炎症调控中的作用及机制研究

Orthodontically induced inflammatory root resorption (OIIRR) is a common and serious consequence of orthodontic tooth movement. OIIRR and orthodontic tooth movement are both osteoimmunologic processes evoked by orthodontic force. In recent years, the immunomodulatory and anti-inflammatory properties of periodontal ligament-derived MSCs(PDLSCs)have been emphasized. Base on the previous researches and the pilot studies of our research group, we speculate that the PDLSCs modulate the local aseptic inflammation of the orthodontic tooth movement, and the imbalance between them might be the pathogenesis of OIIRR. Combining the newly discovered role of TNF-α/NF-κB signaling during osteoimmunologic process and immunomodulation of PDLSCs, our project design is as follow: complete the spectrum of inflammatory cytokines in the periodontal tissue during orthodontic tooth movement; verify the anti-inflammatory properties of PDLSCs in the orthodontic process; explore the mechanism of TNF-α/NF-κB signaling effecting on immunomodulatory properties of PDLSCs. This project would clarify the mechanism of periodontal tissue remodeling based on the balance of the immunomodulatory properties of PDLSCs and the level of inflammation, as well as establish the effective approach to intervene the OIIRR.

正畸炎性牙根吸收（OIIRR）是牙颌畸形矫治中亟待解决的常见并发症。OIIRR及正畸牙移动均是正畸力启动下的骨免疫过程，破骨活动亢进是OIIRR发生的重要原因。牙周膜间充质干细胞（PDLSCs）因其特异的牙周膜分布和对免疫炎症有效的调控能力而倍受关注。申请者前期研究结果提示，PDLSCs的免疫调节能力与牙周局部炎性水平二者之间的失衡可能是OIIRR的重要发生机制。结合最新揭示的TNF-α/NF-κB信号通路在骨免疫及MSCs免疫调节中的重要作用，本项目拟应用正畸牙移动模型完善牙周组织中的炎症因子谱；验证PDLSCs对正畸牙移动牙周局部炎症水平的调控作用；进一步探讨应力刺激下TNF-α/NF-κB信号通路对PDLSCs免疫调节功能的影响机制。该项目为阐明以PDLSCs免疫调节能力与炎症水平平衡为基础的正畸牙移动牙周改建机制及构建基于PDLSCs免疫调节机制的OIIRR的临床干预路径提供依据。

正畸炎性牙根吸收（OIIRR）是牙颌畸形矫治中亟待解决的常见并发症。正畸牙移动和牙根吸收均是正畸力启动下的骨免疫过程，破骨活动亢进是OIIRR发生的重要原因。牙周膜间充质干细胞（PDLSCs）因其特异的牙周膜分布和对免疫炎症有效的调控能力而倍受关注。课题前期研究提示，PDLSCs的免疫调节能力与牙周局部炎性水平二者之间的失衡可能是OIIRR的重要发生机制，IL6/gp130/IL6R信号通路可能通过免疫机制调控破骨活性。本课题重点研究了牙移动过程中牙周膜微环境变化，牙周膜细胞炎性因子表达规律以及机体免疫微环境的改变，探讨炎性因子参与调控牙移动可能的免疫学机制。主要结果：1发现正畸载荷力能“点燃”牙周膜细胞，并促进其表达IL-6，激活下游信号通路。IL-6可以改变破骨和成骨活动从而影响牙移动速率。IL-6可能通过gp130/IL6R介导的JAK/STAT3和SHP2/ras/MAPK通路的切换调节压力侧破骨活性，从而调节正畸牙移动。2正畸牙移动不仅可引起牙周膜局部炎症，而且可以调节Th17细胞和Treg细胞的平衡。提示可通过调节Th17/Treg的平衡来促进正畸牙移动速度。3 P物质能激活并动员机体CD45−CD11b−CD29+MSCs参与颅骨缺损修复并促进体外移植的MSC的存活。 4发现在加力情况下，压力侧和张力侧牙周组织中Gli1的表达增加，且阳性细胞压力侧多于张力侧，颅骨骨缝Gli1+MSC细胞的骨改建能力明显强于BMSC。研究结果为进一步阐明以牙周膜细胞炎性水平与机体免疫活性平衡为基础的正畸牙移动牙周改建机制及构建基于PDLSCs免疫调节机制的正畸骨改建的临床干预路径提供依据。