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

• 批准号: 10708934
• 负责人: Brian Lee Foster
• 金额: $ 50.18万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10708934
• 关键词: Affect; Alkaline Phosphatase; Anions; Ankylosis; Antibody Therapy; Automobile Driving; Biochemical; Biochemistry; Birth; 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; Fracture; Future; Genes; Genetic; Goals; Histology; Human; Hydrolysis; Hypercalcemia; Hypophosphatemia; In Vitro; Incidence; Individual; Inherited; Kidney; Knowledge; Mechanics; Metabolism; Modeling; Mus; Mutation; Nephrocalcinosis; Oral; Oral health; Osteocytes; Osteogenesis; Osteomalacia; Outcome; Pathogenicity; Pathologic; Patients; Periodontal Diseases; Physiologic calcification; Pilot Projects; Production; Property; Protein Dephosphorylation; 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; in vivo; inhibitor; inorganic phosphate; insight; long bone; microCT; mineralization; mouse model; mutant; neutralizing antibody; novel; osteopontin; overexpression; pharmacologic; plasma cell membrane glycoprotein PC-1; pre-clinical; prevent; skeletal; standard of care; therapy design; translational study; treatment effect; wasting

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.

项目摘要/摘要 PHEX基因突变导致X连锁低磷血症(XLH)，这是最常见的遗传性 软骨病。在XLH中，成纤维细胞生长因子23(FGF23)的升高导致肾脏磷酸盐(PI)的浪费， 低磷血症，1，25-二羟基维生素D(1，25D)减少，以及继发性甲状旁腺功能亢进症，都是 导致骨骼和牙列的矿化紊乱。然而，目前的治疗方法缺乏疗效， 目前还没有治疗方法可以特别改善严重影响口腔的相关牙槽缺损症 黄体生成素患者的健康和生活质量。到目前为止治疗效果有限的部分原因是 XLH型矿化缺陷的复杂病因，包括被忽视的局部扰动和 没有解决的问题。XLH的常规治疗，包括口服1，25D和PI，显示有限的改善 骨骼和牙齿缺陷。最近针对过量的FGF23中和抗体(FGF23Ab)的治疗 FGF23有望成为护理的标准。FGF23Ab的临床前和临床试验均未评估 牙齿的牙槽效应。在一项初步研究中，我们发现FGF23Ab在与1，25D类似的情况下，在 XLHHyp小鼠模型的建立。FGF23Ab和1，25D治疗不能解决XLH矿化缺陷 反映了对PHEX功能和XLH病理机制的认识差距，预防了有效的 治疗。目前的治疗方法没有解决XLH中受到干扰的两个矿化调节剂，很可能 通过局部作用于骨骼和牙齿细胞外基质，导致永久性缺陷。PHEX卵裂和 使矿化抑制物骨桥蛋白(OPN)失活。XLH型骨质疏松症患者骨骼和牙齿中骨桥蛋白的增加 矿化作用。此外，无机焦磷酸盐(PPI)的产量增加，这是一种强有力的矿化 抑制物，发生在Hyp小鼠中，与ANK和ENPP1的增加和组织非特异性的降低有关 碱性磷酸酶(TNAP)。因此，全身性(高FGF23，低1，25D和PI)和局部的中断 (OPN和PPI增加)水平导致XLH相关矿化紊乱。当地的因素并没有 到目前为止一直是治疗的目标。TNAP通过降低PPI和促进局部ECM的矿化 去磷酸化和失活骨桥蛋白。该项目旨在为当地矿化提供新的见解。 利用XLH小鼠模型研究牙槽组织中的缺陷，并测试新的治疗方法以防止 并改善这些缺陷。我们假设XLH中OPN和/或PPI的校正是有效的 正常化牙槽骨矿化，改善口腔健康。我们将通过三个目标来检验这一假设：(1) 目的：(2)确定骨桥蛋白在XLH牙槽骨矿化缺陷中的作用。 PPI在XLH牙槽骨矿化缺陷中的致病作用；(3)确定联合OPN的作用 PPI降低对Hyp小鼠牙槽骨愈合的影响。预期结果包括对 XLH的牙槽骨矿化缺陷，对如何针对这些缺陷进行改善具有积极影响 未来在XLH等病理条件下的治疗效果。