Novel Control of FGF23 in Metabolic Bone Disease

FGF23 在代谢性骨疾病中的新控制

基本信息

批准号：
9751286
负责人：
KENNETH E WHITE
金额：
$ 23.26万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-26 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751286
关键词：
Ablation Address Adenine Affect Alleles Anemia Automobile Driving Binding Biological Biology Bone Diseases Bone Marrow Calcinosis Cell Line Cell physiology Cells Chronic Kidney Failure Clinical Data Dialysis procedure Diet Disease Disease Progression Disease model Dose Elements Endocrine Endocrine System Diseases Erythropoiesis Erythropoietin Familial hypophosphatemic bone disease Feedback Fracture Genes Hematopoietic Hematopoietic stem cells Heritability Homeostasis Hormones Human Hypophosphatemia Hypoxia In Vitro Individual Iron Kidney Kidney Diseases Kidney Failure Knock-in Mouse Knowledge Late-Onset Disorder Lead Light Link Marrow Mediating Mendelian disorder Messenger RNA Metabolic Metabolic Bone Diseases Metabolism Minerals Molecular Morbidity - disease rate Mus Onset of illness Osteoblasts Osteocytes Osteomalacia Outcome Pathway interactions Patients Population Pregnancy Production Proteins Puberty Regulation Replacement Therapy Resistance Rickets Risk Factors Rodent Secondary to Serum Severities Severity of illness Signal Transduction Site Stimulus Sum Syndrome System Testing Therapeutic Work adverse outcome bone bone cell bone loss cell type cortical bone disease phenotype fibroblast growth factor 23 fracture risk gain of function mutation in vivo inhibitor/antagonist inorganic phosphate insight iron deficiency iron metabolism mRNA Expression modifiable risk mortality mouse model new therapeutic target novel patient population positional cloning promoter response skeletal skeletal disorder tumor wasting

项目摘要

Project Summary/Abstract: We identified Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene for autosomal dominant hypophosphatemic rickets (ADHR), characterized by hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia and fracture. We made key mechanistic connections regarding the regulation of FGF23 expression by crossover iron and phosphate metabolism, showing that anemia caused late-onset ADHR in a mouse knock-in model of this disease. These findings significantly modify the current endocrine feedback paradigms, determining that biological stimuli outside of the known effectors of FGF23 control, namely anemia, could drive FGF23 production. Therefore, the molecular mechanisms by which FGF23 is regulated and controls phosphate handling are incompletely understood. This work is relevant to chronic kidney disease-mineral bone disorder (CKD- MBD), the largest patient population with co-disturbances in phosphate handling (markedly increased FGF23 leading to metabolic bone disease) and iron metabolism (progressive anemia as the kidneys fail) leading to increased fracture risk and mortality. Our novel preliminary data now make a link between these metabolic systems by demonstrating that erythropoietin (EPO) delivery, a cornerstone therapy for anemia in CKD-MBD, markedly elevated bone Fgf23 mRNA and circulating FGF23 protein in mice. Further, these increases occur by over-riding mechanisms that typically inhibit FGF23 production. Using a recently developed mouse model carrying conditional flox-Fgf23 alleles, our initial findings also support that EPO control of FGF23 may occur in bone cells outside of the ‘traditional’ expression sites of osteoblasts/osteocytes, thus potentially revealing novel regulatory systems for phosphate metabolism. In light of these new results, the molecular mechanisms dictating EPO-mediated FGF23 regulation during kidney disease onset and progression, remain to be defined. The central hypothesis for this proposal is: FGF23 is stimulated by EPO in osteoblasts/osteocytes and in hematopoietic progenitor cells leading to altered mineral metabolism. This axis may be a modifiable risk factor in CKD-MBD, therefore we expect our fundamental biological discoveries to provide novel translational insight into rare and common syndromes of altered FGF23 expression, and into the basic biology of phosphate metabolism.

项目摘要/摘要：我们在定位克隆中鉴定出了成纤维细胞生长因子 23 (FGF23) 分离常染色体显性低磷血症性佝偻病 (ADHR) 基因的方法，其特征是继发于肾磷酸盐消耗、佝偻病/骨软化症和骨折的低磷血症我们做出了关键。铁和磷酸盐交叉调节 FGF23 表达的机制联系代谢，表明贫血在小鼠敲入模型中导致迟发性 ADHR。这些发现显着改变了当前的内分泌反馈范式，确定了生物 FGF23 控制的已知效应器之外的刺激（即贫血）可以驱动 FGF23 的产生。因此，FGF23 调节和控制磷酸盐处理的分子机制是这项工作与慢性肾病-矿物质骨病（CKD-）相关。 MBD），磷酸盐处理中存在共扰的最大患者群体（显着增加 FGF23 导致代谢性骨病）和铁代谢（肾脏衰竭导致进行性贫血）导致骨折风险和死亡率增加，现在我们的新初步数据将这些因素联系起来。通过证明促红细胞生成素 (EPO) 输送（EPO 是治疗贫血的基础疗法）来改善代谢系统 CKD-MBD，小鼠中骨 Fgf23 mRNA 和循环 FGF23 蛋白显着升高。增加是通过超越通常抑制 FGF23 产生的机制而发生的。开发了携带条件 flox-Fgf23 等位基因的小鼠模型，我们的初步研究结果也支持 EPO FGF23 的控制可能发生在“传统”表达位点之外的骨细胞中成骨细胞/骨细胞，因此有可能揭示磷酸盐代谢的新调节系统。根据这些新结果，决定 EPO 介导的 FGF23 调节的分子机制肾脏疾病的发病和进展仍有待确定。该提案的中心假设是： FGF23 受成骨细胞/骨细胞和造血祖细胞中的 EPO 刺激，导致该轴可能是 CKD-MBD 的一个可改变的危险因素，因此我们期望我们的结果基础生物学发现为罕见和常见综合征提供新的转化见解改变 FGF23 表达，并进入磷酸盐代谢的基础生物学。