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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.

项目总结/文摘