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

项目总结/摘要 PHEX基因突变导致X连锁低磷酸盐血症（XLH），这是遗传性低磷酸盐血症最常见的形式。 软骨病。在XLH中，升高的成纤维细胞生长因子23（FGF 23）导致肾磷酸盐（Pi）消耗， 低磷酸盐血症、1，25-二羟维生素D（1，25 D）减少和继发性甲状旁腺功能亢进，所有 导致骨骼和齿系的矿化紊乱。然而，目前的治疗缺乏疗效， 没有治疗可用于具体改善显著影响口腔的相关牙槽缺损 XLH患者的健康和生活质量。迄今为止，治疗的有限疗效部分与 XLH矿化缺陷的复杂病因，包括被忽视的局部扰动， 没有地址XLH的常规治疗，包括口服1，25 D和Pi，显示出有限的改善 骨骼和牙齿的缺陷最近的FGF 23中和抗体（FGF 23 Ab）治疗靶向过量的 FGF 23有望成为标准治疗。未评价FGF 23 Ab的临床前或临床试验 牙槽效应在一项初步研究中，我们发现FGF 23 Ab在治疗中的改善有限，类似于1，25 D。 XLH的Hyp小鼠模型。FGF 23 Ab和1，25 D治疗不能解决XLH矿化缺陷 反映了关于PHEX功能和XLH病理机制的知识差距， 治疗。目前的治疗方法没有解决XLH中受到干扰的两种矿化调节剂， 通过局部作用于骨和牙齿细胞外基质而导致持续性缺损。PHEX裂解， 灭活矿化抑制剂骨桥蛋白（OPN）。XLH中骨骼和牙齿中OPN的增加抑制了 成矿此外，无机焦磷酸盐（PPi）的产生增加， 抑制剂，发生在Hyp小鼠与增加ANK和ENPP 1，和减少组织非特异性 碱性磷酸酶（TNAP）。因此，系统性（高FGF 23，低1，25 D和Pi）和局部性（高FGF 23，低1，25 D和Pi）的破坏都是可能的。 （增加的OPN和PPi）水平有助于XLH相关的矿化障碍。地方因素没有 迄今为止的治疗目标。TNAP通过降低PPi和PPi促进局部ECM中的矿化， 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， 并改善这些缺陷。我们假设，XLH中OPN和/或PPi的纠正是有效治疗的必要条件。 使牙槽骨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一假设：（1） 探讨骨桥蛋白在XLH牙槽骨矿化缺陷中的作用; PPi在XLH牙槽骨矿化缺陷中的作用;（3）确定联合OPN的作用 降低PPi对Hyp小鼠牙槽骨愈合的影响。预期成果包括： XLH中的牙槽骨矿化缺陷，积极影响如何针对这些缺陷进行改善 治疗效果XLH和其他病理条件的未来。

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.