Dvl蛋白交叉调控Wnt/β-catenin和NF-κB对炎性关节炎骨侵蚀的作用机制及研究

我们立足前期3项国家自然科学基金研究提示：Wnt/β-catenin和NF-κB是炎性关节炎骨侵蚀关键信号通路，Dishevelled（Dvl）具有活化Wnt通路，抑制NF-κB炎症效应、加强成骨同时抑制破骨，维持骨代谢稳态。本研究拟开展：①从基因和蛋白层面观察Dvl激活Wnt信号通路，上调成骨活性；同时抑制NF-κB介导的"炎症因子风暴"，调控骨代谢。②构建siRNA，转染C2C12细胞和破骨前体细胞，揭示成骨和破骨细胞调控机制，探究Dvl通过经典Wnt3A途径调控破骨细胞分化和骨重建机制，③在TNFα转基因关节炎小鼠，验证Dvl诱导关节β-catenin表达，协同P65抑制NF-κB活性，通过上调OB和抑制OC，维持关节骨代谢稳态，力图揭示Dvl在炎性关节炎小鼠骨侵蚀作用及其机制。本研究不仅阐明Dvl功能和调控机制，而且为研究Wnt/NF-κB双通道药物靶点增添新武器。

The previous three researches of ours supported by NSFC reveal that:The NF-κB and Wnt/β-catenin signal pathway play an important role in bone erosion induced by inflammatory arthritis. Recently,the Dishevelled(Dvl) has been recongized as the key point in the regulation of Wnt signal pathway,which stimulates the Wnt and upregulate the OB function,on the other hand,downregulate the OC due to inhibiting the NF-κB signal pathway.The strategies of present study are that:①To analyse regulating effect of Dvl on Wnt and NF-κB from gene and protein levels,aiming to demonstrate Dvl generate the dual function which upregulate Wnt pathway and represses NF-κB induced "inflammatory cascade".②To construct the siRNA and transfect it into C2C12 and preosteoclast in order to elucidate the mechanism of Dvl interference between the differentation of osteoblast and reconstruction of osteoclast by canonical Wnt3A signal pathway.③To demonstrate the Dvl goading the expression of β-catenin which inhibite the NF-κB activation through cooperating with P65 in TNFαtransgenomic arthritic murine model.The physiological function of Dvl maintain the homeostasis of bone metabolism which protect the OB and repress the OC by regulation of dual signal pathway，we are striving to clarify the function and mechanism of Dvl on the bone erosion of arthritic murine.The present study elucidate the function and mechanism of Dvl in Wnt/NF-κB signal pathway which held up the basic ponits to develop a new treatment strategies on bone erosion.