Identifying Novel Mechanisms for Dentoalveolar Mineralization Defects in X-linked Hypophosphatemia

确定 X 连锁低磷血症中牙槽矿化缺陷的新机制

基本信息

批准号：
10564142
负责人：
Brian Lee Foster
金额：
$ 52.35万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564142
关键词：
Affect Alkaline Phosphatase Anions Ankylosis Automobile Driving Biochemical Biochemistry Birth Clinical Clinical Trials Complex Defect Deformity Dental Dental Enamel Dental Pulp Exposure Dentin Dentin Formation Dentition Dihydroxycholecalciferols Diphosphates Disease Epiphysial cartilage Etiology Extracellular Matrix Extracellular Matrix Proteins Familial hypophosphatemic bone disease Future Genes Genetic Goals Histology Human Hydrolysis Hypercalcemia Hypophosphatemia In Vitro Incidence Individual Inherited Kidney Knowledge Lead Mechanics Metabolism Modeling Mus Mutation Oral Oral health Osteocytes Osteogenesis Osteomalacia Outcome Pathogenicity Pathologic Patients Pharmacology Pilot Projects Production Property Proteins Quality of life Rickets Role Secondary Hyperparathyroidism Serum Skeleton Testing Thinness Tissues Tooth Loss Tooth structure Treatment Efficacy alveolar bone bone bone healing conventional therapy dental abscess design effective therapy fibroblast growth factor 23 healing improved inhibitor inorganic phosphate insight long bone microCT mineralization mouse model mutant mouse model neutralizing antibody novel osteopontin plasma cell membrane glycoprotein PC-1 pre-clinical prevent skeletal standard of care therapy design translational study treatment effect wasting

项目摘要

PROJECT SUMMARY/ABSTRACT Mutations in the PHEX gene cause X-linked hypophosphatemia (XLH), the most common form of hereditary rickets. In XLH, elevated fibroblast growth factor 23 (FGF23) causes renal phosphate (Pi) wasting, hypophosphatemia, reduced 1,25-dihydroxyvitamin D (1,25D), and secondary hyperparathyroidism, all contributing to mineralization disturbances in the skeleton and dentition. Yet current treatments lack efficacy and no treatments are available to specifically improve associated dentoalveolar defects that substantially affect oral health and quality of life in individuals with XLH. Limited efficacy of treatments to date is in part related to the complex etiology of mineralization defects in XLH, including local perturbations that have been overlooked and gone unaddressed. Conventional therapy for XLH, consisting of oral 1,25D and Pi, shows limited improvement of skeletal and dental defects. A recent FGF23-neutralizing antibody (FGF23Ab) treatment targeting excess FGF23 is poised to become standard-of-care. Neither preclinical nor clinical trials of FGF23Ab evaluated dentoalveolar effects. In a pilot study, we found FGF23Ab made limited improvements similar to 1,25D in the Hyp mouse model of XLH. The inability of FGF23Ab and 1,25D therapies to resolve XLH mineralization defects reflects gaps in knowledge about functions of PHEX and pathological mechanisms of XLH, preventing effective treatments. Two mineralization regulators disturbed in XLH are not addressed by current treatments and likely contribute to persistent defects by acting locally in bone and tooth extracellular matrices. PHEX cleaves and inactivates mineralization inhibitor, osteopontin (OPN). Increased OPN in bones and teeth in XLH inhibits mineralization. Additionally, increased production of inorganic pyrophosphate (PPi), a potent mineralization inhibitor, occurs in Hyp mice in association with increased ANK and ENPP1, and decreased tissue-nonspecific alkaline phosphatase (TNAP). Thus, disruptions at both systemic (high FGF23, low 1,25D and Pi) and local (increased OPN and PPi) levels contribute to XLH-associated mineralization disorders. Local factors have not been targeted by treatments to date. TNAP promotes mineralization in local ECM by both reducing PPi and dephosphorylating and inactivating OPN. This project is designed to provide new insights into local mineralization defects in dentoalveolar tissues using a mouse model of XLH, and to test novel treatment approaches to prevent and ameliorate those defects. We hypothesize that correction of OPN and/or PPi in XLH is required to effectively normalize dentoalveolar mineralization and improve oral health. We will test this hypothesis by three aims: (1) To establish the contribution of OPN to dentoalveolar mineralization defects in XLH; (2) To determine the pathogenic role of PPi in dentoalveolar mineralization defects in XLH; (3) To define effects of combined OPN and PPi reduction on Hyp mouse dentoalveolar healing. Expected outcomes include new insights into dentoalveolar mineralization defects in XLH, positively impacting how these may be targeted for improving treatment effects in XLH and other pathological conditions the future.

项目概要/摘要 PHEX 基因突变导致 X 连锁低磷血症 (XLH)，这是遗传性贫血的最常见形式疳。在 XLH 中，成纤维细胞生长因子 23 (FGF23) 升高会导致肾磷酸盐 (Pi) 消耗，低磷血症、1,25-二羟基维生素 D (1,25D) 减少和继发性甲状旁腺功能亢进症，所有这些导致骨骼和牙列矿化紊乱。然而目前的治疗方法缺乏疗效并且没有治疗方法可以专门改善严重影响口腔的相关牙槽骨缺陷 XLH 患者的健康和生活质量。迄今为止治疗效果有限部分与 XLH 矿化缺陷的复杂病因，包括被忽视的局部扰动没有得到解决。 XLH 的常规疗法包括口服 1,25D 和 Pi，但效果有限骨骼和牙齿缺陷。最近的 FGF23 中和抗体 (FGF23Ab) 治疗针对过量 FGF23 有望成为护理标准。 FGF23Ab 的临床前试验和临床试验均未评估牙槽效应。在一项试点研究中，我们发现 FGF23Ab 在 XLH 的 Hyp 小鼠模型。 FGF23Ab 和 1,25D 疗法无法解决 XLH 矿化缺陷反映了有关 PHEX 功能和 XLH 病理机制的知识差距，阻碍了有效的治疗。目前的治疗方法并未解决 XLH 中受到干扰的两种矿化调节因子，并且可能通过在骨和牙齿细胞外基质中局部作用而导致持续性缺陷。 PHEX 裂解和使矿化抑制剂骨桥蛋白 (OPN) 失活。 XLH 中骨骼和牙齿中 OPN 的增加抑制矿化。此外，无机焦磷酸盐 (PPi) 的产量增加，这是一种有效的矿化作用抑制剂，发生在 Hyp 小鼠中，与 ANK 和 ENPP1 增加以及组织非特异性减少相关碱性磷酸酶（TNAP）。因此，系统性（高 FGF23、低 1,25D 和 Pi）和局部的破坏（增加的 OPN 和 PPi）水平会导致 XLH 相关的矿化障碍。当地因素还没有迄今为止已成为治疗的目标。 TNAP 通过降低 PPi 和使 OPN 去磷酸化和失活。该项目旨在为当地矿化提供新的见解使用 XLH 小鼠模型研究牙槽组织缺陷，并测试新的治疗方法以预防并改善这些缺陷。我们假设 XLH 中的 OPN 和/或 PPi 的校正需要有效地使牙槽矿化正常化并改善口腔健康。我们将通过三个目标来检验这个假设：（1）确定 OPN 对 XLH 牙槽骨矿化缺陷的贡献； (2) 确定 PPi 在 XLH 牙槽骨矿化缺陷中的致病作用； (3) 定义组合 OPN 的效果和 PPi 减少对 Hyp 小鼠牙槽愈合的影响。预期成果包括对以下方面的新见解 XLH 中的牙槽骨矿化缺陷，对如何针对改善这些缺陷产生积极影响 XLH 和其他病理状况未来的治疗效果。