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.

项目摘要 X连锁低磷血症是最常见的遗传性软骨病，其临床特征为 骨骼矿化受损，循环磷酸盐水平低。XLH是由基因突变引起的 与X染色体(PHEX)基因上的内肽酶同源的磷酸盐调节基因， 这会导致促磷激素、成纤维细胞生长因子23(FGF23)水平升高，以及 随之而来的是肾脏磷酸盐消耗。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，以及不良的牙周韧带。 依恋。尽管已经开发了新的治疗策略来阻断FGF23的活性并增加 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了 这种硬化素抗体治疗降低了FGF23并增加了循环中的磷酸盐水平。这些系统性的 这些变化与Hyp轴骨中骨量和矿化水平的增加有关 老鼠。在目前的方案中，我们建议检验硬化素是XLH的重要介体的假设。 相关的牙周病和抑制硬化素活性会改善牙周炎。这 这一假说建立在已发表的描述硬化素和Wnt信号在脑出血中的重要性的报道上。 矿化组织的发育，包括牙周组织。此外，我们的初步数据已经 硬化素抗体治疗可改善牙槽骨量和牙周膜 Hyp小鼠的依恋。为了验证我们的假设，我们将分析是否通过 遗传和药物策略都改善了Hyp小鼠的牙周缺陷(目标1)和 探讨硬化素在牙囊前体细胞成骨分化中的作用 2)。如果成功，目前的建议将进一步加深我们对牙周炎病理生理学的了解 并提供了关于硬化素抗体使用的翻译数据，该抗体是最近FDA批准的一种 药物治疗。此外，该提案将有助于建立专门知识和初步数据 这是罗斯博士在牙科和颅面研究领域竞争未来R01级资金所必需的。