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: 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
• 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

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基因中的突变引起X连锁性低磷酸血症（XLH），这是遗传的最常见形式 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）浪费， 低磷酸血症，减少1,25-二羟基维生素D（1,25D）和继发性甲状旁腺功能亢进症 造成骨骼和牙列的矿化干扰。然而，目前的治疗缺乏功效和 没有治疗可用于特异性地改善基本影响口腔的相关牙皮肺泡缺陷 XLH患者的健康和生活质量。迄今为止治疗的功效有限，部分与 XLH中矿化缺陷的复杂病因，包括被忽视的局部扰动和 尚未解决。由口服1,25D和PI组成的XLH的常规疗法显示出有限的改进 骨骼和牙齿缺陷。最近的FGF23中和抗体（FGF23AB）治疗的一种针对多余的治疗 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 齿状肺泡效应。在一项试点研究中，我们发现FGF23AB的改进有限，类似于1,25D XLH的催眠小鼠模型。 FGF23AB和1,25D疗法无法解决XLH矿化缺陷 反映有关PHEX功能和XLH病理机制知识的差距，以防止有效 治疗。目前的处理并未解决两个在XLH中受到干扰的矿化调节剂，并且很可能 通过在骨骼和牙齿外矩阵中局部作用来导致持续缺陷。 PHEX切割和 使矿化抑制剂，骨桥蛋白（OPN）灭活。 XLH抑制骨骼和牙齿的OPN增加 矿化。另外，增加了无机焦磷酸盐（PPI）的产生，这是一种有效的矿化 抑制剂发生在催眠小鼠中，随着ANK和ENPP1的增加而发生，并降低了非特异性的组织 碱性磷酸酶（TNAP）。因此，全身性的破坏（高FGF23，低1,25D和PI）和局部 （OPN和PPI的增加）水平有助于与XLH相关的矿化疾病。当地因素尚未 迄今已受到治疗的针对性。 TNAP通过减少PPI和 去磷酸化和灭活OPN。该项目旨在为当地矿化提供新的见解 使用XLH的小鼠模型在牙道肺泡组织中的缺陷，并测试新的治疗方法以防止 并改善这些缺陷。我们假设需要在XLH中对OPN和/或PPI进行校正以有效地 标准化齿状肺泡矿化并改善口腔健康。我们将通过三个目的检验这一假设：（1） 建立OPN对XLH中牙道肺泡矿化缺陷的贡献； （2）确定 PPI在XLH中PPI中的致病作用； （3）定义联合OPN的效果 PPI降低了催眠小鼠齿状肺泡愈合。预期的结果包括对 XLH中的齿状肺泡矿化缺陷，积极影响这些缺陷如何针对改善 XLH和其他病理状况的治疗效果未来。