Assessing the function role of sclerostin in periodontal disease in XLH

项目摘要 X连锁低磷血症（XLH）是遗传性佝偻病的最常见形式，其临床特征是 受损的骨骼矿化和低循环磷酸盐水平。XLH是由一个突变引起的， 与位于X染色体上的内肽酶（PHEX）基因同源的磷酸调节基因， 导致促磷酸激素、成纤维细胞生长因子23（FGF 23）水平升高， 随后肾磷酸盐消耗。XLH患者还存在各种牙周缺陷， 包括牙槽骨和牙骨质的异常矿化，以及牙周韧带的不良 附件.尽管已经开发了阻断FGF 23活性并增加FGF 23表达的新的治疗策略， 牙周病是一种常见的牙周病。我们的实验室最近证明 sclerostin抗体治疗减少FGF23并增加循环磷酸盐水平。这些系统性 这些变化与Hyp中轴骨骨量和矿化水平的增加有关。 小鼠在目前的提议中，我们提出测试硬化蛋白是XLH的重要介质的假设。 与牙周病相关，抑制sclerostin活性将改善牙周炎。这 这一假设建立在已发表的描述硬化蛋白和Wnt信号传导在骨形成中的重要性的报告上。 包括牙周组织在内的矿化组织的发育。此外，我们的初步数据显示， 表明sclerostin抗体治疗可改善牙槽骨质量和牙周韧带 在Hyp小鼠中的附着。为了验证我们的假设，我们将分析通过抑制硬化蛋白活性是否可以抑制硬化蛋白活性。 遗传和药物策略都改善了Hyp小鼠的牙周缺陷（Aim 1）， 确定硬化蛋白在牙囊祖细胞（DFPCs，Aim）成骨分化中的作用 2）。如果成功的话，目前的建议将进一步加深我们对牙周炎的病理生理学的理解， XLH并提供了使用硬化蛋白抗体的翻译数据，硬化蛋白抗体是最近FDA批准的 药物治疗。此外，该提案将有助于建立专门知识和初步数据， 罗斯博士有必要在牙科和颅面研究中竞争未来的R01级资金。

Project Summary X-linked hypophosphatemia (XLH) is the most common form of heritable Rickets, characterized clinically by impaired skeletal mineralization and low circulating phosphate levels. XLH is caused by a mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX) gene, which leads to elevated levels of the phosphotropic hormone, fibroblast growth factor 23 (FGF23), and subsequently renal phosphate wasting. XLH patients also present with a variety of periodontal defects, including aberrant mineralization of both the alveolar bone and cementum, as well as poor periodontal ligament attachment. Although novel treatment strategies have been developed that block FGF23 activity and increase phosphate levels, periodontal disease remains a clinical concern. Our laboratory has recently demonstrated that sclerostin antibody treatment reduces FGF23 and increases circulating phosphate levels. These systemic changes were associated with increased bone mass and mineralization levels in the axial skeleton of Hyp mice. In the current proposal we propose to test the hypothesis that sclerostin is an important mediator of XLH- related periodontal disease and that suppression of sclerostin activity will improve periodontitis. This hypothesis is built on published reports describing the importance of sclerostin and Wnt-signaling in the development of mineralized tissues, including the periodontium. Further, our preliminary data has demonstrated that sclerostin antibody treatment improves alveolar bone mass and periodontal ligament attachment in Hyp mice. To test our hypothesis, we will analyze whether suppressing sclerostin activity via both genetic and pharmaceutical strategies improves the periodontal defects in Hyp mice (Aim 1) and determine the role of sclerostin in the osteogenic differentiation of dental follicle progenitor cells (DFPCs, Aim 2). If successful, the current proposal will further our understanding of the pathophysiology of periodontitis in XLH and provide translational data on the use of a sclerostin antibody, a recently FDA-approved pharmaceutical treatment. Further, the proposal will serve to build the expertise and preliminary data necessary for Dr. Ross to compete for future R01-level funding in dental and craniofacial research.