Sclerostin通过WNT与MAPK信号通路调控牙周炎症破坏与修复的机制研究

Since periodontitis is one of the crucial challenges orthodontists have to face when treating adult patients, it is very important to study the pathogenesis of periodontitis in order to reach the goal of moving teeth safely and effectively. Some studies concluded that Sclerostin, as an inhibitor of canonical WNT signaling pathway, increases significantly in both periodontal tissue and serum of periodontitis patient. However it is still unclear about the biological mechanism. Our previous research found that lacking of Sclerostin can inhibit the process of periodontitis, protect alveolar bone from destruction, and reduce the phosphorylation of ERK1/2 in periodontal tissue. Considering the role of WNT and MAPK pathway in regulating osteogenic differentiation of periodontal ligament stem cells and the effect of ERK1/2 pathway in promoting inflammatory factors, we infer Sclerostin is crucial in the destruction and rehabilitation of periodontitis via WNT and MAPK pathway. In this study, we established experimental periodontitis model in SOST KO mice and analyzed the levels of inflammatory factors，osteoclastic factors and pathway signals in vivo. In vitro, we investigated the signaling mechanism of Sclerostin on osteogenic differentiation of PDLCs and inflammation reaction of osteoblast via gene tranfection and pathway inhibition. Therefore, this study will thoroughly investigate the biological mechanism of Sclerostin in periodontitis and lay the foundation of clinical application of Sclerostin related biological agents.

牙周炎是成人患者接受正畸治疗的最大障碍之一，深入研究牙周炎的发病机制对于实现安全有效的牙移动具有重要意义。有研究证实，经典WNT信号通路抑制剂Sclerostin在牙周炎患者的局部组织与血清中表达明显升高，但其生物学作用尚不明确。申请者前期研究发现：Sclerostin缺失能够抑制牙周炎的炎症破坏，降低牙周组织内ERK1/2的磷酸化。结合WNT与MAPK通路调控牙周膜干细胞成骨向分化以及ERK1/2通路促进炎症因子释放的特点，我们推断Sclerostin能通过这两条通路在牙周炎的炎症与修复中发挥关键作用。为了验证该假说，申请者在体内建立SOST-/-小鼠牙周炎模型，体外培养牙周膜干细胞与成骨细胞，通过基因转染、信号通路阻断等手段深入研究sclerostin调控牙周炎炎症与修复的生物学机制。本课题将进一步揭示牙周炎的生物学机理，为Sclerostin生物制剂在其中的临床转化应用奠定理论基础。