DMP1通过FGF-23/Pi/β-catenin功能轴调控下颌骨髁突软骨细胞成骨分化的机制研究

下颌骨髁突是颞下颌关节重要的组成部分，对于咀嚼、发音及颌面部生长发育具有重要作用，其具体调控机制仍未清楚。DMP1对骨生长发育及矿物质代谢调节具有重要调控作用。申请人前期研究发现Dmp1KO小鼠明显升高血清FGF-23及低血磷、下颌骨髁突发育畸形且过表达β-Catenin，提示Dmp1KO小鼠下颌骨髁突发育与Wnt/β-catenin信号通路密切相关，但具体作用机制尚不清楚。因此，本项目拟在前期工作的基础上，建立两组转基因小鼠模型探究DMP1对于下颌骨髁突成软骨及软骨细胞成骨分化的作用。另外，通过体外下颌骨髁突组织培养、Wnt/β-catenin信号通路抑制剂及FGF-23中和抗体挽救实验，在细胞及分子水平深入探究DMP1对下颌骨髁突软骨细胞成骨分化的调控作用及相关机制。本研究成果将对阐明DMP1对下颌骨髁突发育的调控机制具有重要意义，为临床上治疗牙颌面畸形提供新的靶点。

Mandibular condyle is considered to be crucial part of temporomandibular joint, playing a key role in mastication, pronunciation and the development of maxillofacial development. However, the underlying mechanism is still unknown. DMP1 protein is highly expressed in mineral tissue, which is critical for normal bone formation and mineral metabolism. Our previous study found that Dmp1KO mice displayed significant increased FGF23,low serum Pi level, a drastically malformed TMJ condyle phenotype and β-catenin over-expression,implying that the development of mandibular condyle in Dmp1KO mice is closely related to Wnt/β-catenin signaling pathway. However, the specific role and mechanism of DMP1 in mandibular condylar development are still unknown. Thus, compound transgenic mouse models are used for exploring the role of DMP1 on the cell transdifferentiation from mandibular condylar chondrocytes into bone cells.Moreover,mandibular condyle culture in vitro experiment, administrations of Wnt/β-catenin signaling inhibitor and anti-FGF23 neutralizing antibodies rescue studies analyze the specific molecular mechanism of the role of DMP1 in mandibular condylar chondrogenesis and cell transformation from chongdrocytes to bone cells. This study will help to reveal the regulatory role and mechanism of DMP1 for mandibular condylar development,thus supplying gene targets for treatment of dento-maxillofacial deformity.