Assessing the function role of sclerostin in periodontal disease in XLH

评估硬化素在 XLH 牙周病中的功能作用

• 批准号: 10303753
• 负责人: Ryan Dee Ross
• 金额: $ 16.75万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303753
• 关键词: Affect; Alveolar; Antibodies; Antibody Therapy; Area; Automobile Driving; Biology; Cell Differentiation process; Cells; Cementocyte; Clinical; Collaborations; Complex; Data; Defect; Dental; Dental Cementum; Dental Pulp; Dental Sac; Dentin; Development; Disease; Endopeptidases; Event; Experimental Models; FDA approved; Familial hypophosphatemic bone disease; Foundations; Functional disorder; Funding; Future; Genes; Genetic; Goals; Heritability; High Prevalence; Hormones; Hypophosphatemia; Impairment; Individual; Kidney; Laboratories; Measures; Mediator of activation protein; Minerals; Mus; Mutation; Osteocytes; Osteogenesis; Outcome; Pathology; Patients; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Pharmacologic Substance; Pharmacology; Physiologic calcification; Plant Roots; Process; Production; Proteins; Publishing; Reporting; Research; Rickets; Role; Signal Transduction; Skeleton; Structure; Symptoms; Testing; Therapeutic; Thick; Time; Tissues; Tooth Diseases; Tooth structure; Training; WNT Signaling Pathway; Work; X Chromosome; alveolar bone; bone; bone mass; craniofacial; fibroblast growth factor 23; fracture risk; gain of function mutation; genetic approach; high risk; improved; improved outcome; inorganic phosphate; loss of function; loss of function mutation; mineralization; mouse model; neutralizing antibody; novel; osteogenic; prevent; skeletal; stem cells; treatment strategy; wasting

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.

项目概要 X连锁低磷血症（XLH）是遗传性佝偻病最常见的形式，临床特征为 骨骼矿化受损和循环磷酸盐水平低。 XLH是由基因突变引起的 与位于X染色体上的内肽酶同源的磷酸调节基因（PHEX）基因， 这会导致促磷酸激素、成纤维细胞生长因子 23 (FGF23) 和 随后肾磷酸盐消耗。 XLH患者还存在多种牙周缺陷， 包括牙槽骨和牙骨质的异常矿化，以及牙周膜的​​不良 依恋。尽管已经开发出新的治疗策略来阻断 FGF23 活性并增加 磷酸盐水平，牙周病仍然是临床关注的问题。我们的实验室最近证明 硬化蛋白抗体治疗可减少 FGF23 并增加循环磷酸盐水平。这些系统性的 变化与 Hyp 中轴骨骼的骨量和矿化水平增加有关 老鼠。在当前的提案中，我们建议检验以下假设：硬化素是 XLH- 的重要介质。 相关的牙周病，并且抑制硬化蛋白活性将改善牙周炎。这 假设是建立在已发表的报告的基础上的，这些报告描述了硬化蛋白和 Wnt 信号传导在 矿化组织的发育，包括牙周组织。此外，我们的初步数据有 证明硬化素抗体治疗可改善牙槽骨质量和牙周膜 Hyp 小鼠的附着。为了检验我们的假设，我们将分析是否通过抑制硬化素活性 遗传和药物策略均可改善 Hyp 小鼠的牙周缺陷（目标 1） 确定硬化素在牙囊祖细胞（DFPCs，Aim 2）。如果成功，当前的提议将进一步加深我们对牙周炎病理生理学的理解 XLH 并提供有关使用 sclerostin 抗体（最近 FDA 批准的一种药物）的转化数据 药物治疗。此外，该提案将有助于建立专业知识和初步数据 这对于 Ross 博士竞争未来牙科和颅面研究领域的 R01 级资金来说是必要的。