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: 10454382
• 负责人: Ryan Dee Ross
• 金额: $ 16.14万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454382
• 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; antagonist; 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.

项目摘要 X连锁低磷血症（XLH）是可遗传的rick鼠的最常见形式，在临床上以 骨骼矿化和低循环磷酸盐水平受损。 XLH是由突变引起的 磷酸盐与位于X染色体（PHEX）基因上的内肽酶同源性的基因调节基因， 这导致磷酸激素的水平升高，成纤维细胞生长因子23（FGF23）和 随后肾磷酸盐浪费。 XLH患者还出现多种牙周缺陷， 包括牙槽骨和牙骨质的异常矿化，以及牙周韧带较差 依恋。尽管已经开发出了阻止FGF23活性并增加的新型治疗策略 磷酸盐水平，牙周疾病仍然是临床问题。我们的实验室最近证明了 这种硬化蛋白抗体治疗可降低FGF23并增加循环磷酸盐水平。这些系统性 变化与hyp的轴向骨骼中的骨骼质量和矿化水平增加有关 老鼠。在当前的提案中，我们提出的是测试硬化蛋白是XLH-重要介体的假设 相关的牙周疾病和硬化蛋白活性的抑制作用将改善牙周炎。这 假设建立在已发表的报告上，描述了硬化蛋白的重要性和wnt信号 矿化组织的发展，包括牙周。此外，我们的初步数据 证明硬化蛋白抗体治疗可改善牙槽骨质量和牙周韧带 催眠小鼠的附着。为了检验我们的假设，我们将分析是否通过 遗传和药物策略都改善了催眠小鼠的牙周缺陷（AIM 1）和 确定硬化蛋白在牙卵泡祖细胞的成骨分化中的作用（DFPC，AIM 2）。如果成功，当前的建议将进一步了解我们对牙周炎的病理生理学的理解 XLH并提供有关使用硬化蛋白抗体的翻译数据，该抗体最近批准了FDA 药物治疗。此外，该提案将有助于建立专业知识和初步数据 罗斯博士在牙齿和颅面研究中争夺未来R01级资金所必需的。