Control of FGF23 Bioactivity via Circulating alpha-Klotho

通过循环 α-Klotho 控制 FGF23 生物活性

基本信息

批准号：
8636471
负责人：
KENNETH E WHITE
金额：
$ 33.93万
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：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8636471
关键词：
Affect Animals Binding Proteins Biochemical Biological Biology Blood Bone Diseases Bone Mineral Contents Calcinosis Calcitriol Cell physiology Cell surface Cells Chromosomal translocation Chronic Kidney Failure Clinical Complex Diet Disease Endocrine Etiology Exhibits FGFR1 gene Familial hypophosphatemic bone disease Feedback Fibroblast Growth Factor Receptors Fracture Genes Health Homeostasis Hormonal Hyperparathyroidism Hypophosphatemia In Vitro Individual Kidney Knockout Mice Lead Mediating Membrane Messenger RNA Metabolic Bone Diseases Metabolism Minerals Modeling Molecular Mus Organ Osteomalacia Pathway interactions Patients Phenocopy Plasma Play Process Production Protein Isoforms Recombinants Regulation Resistance Rickets Role Secondary to Serum Serum Proteins Signal Transduction Skeleton Staging Syndrome System Testing Therapeutic Tissues Vitamin D2 Wild Type Mouse Work bone bone cell disease phenotype extracellular fibroblast growth factor 23 gain of function mutation gene function in vivo inhibitor/antagonist inorganic phosphate insight loss of function mutation mortality new therapeutic target novel positional cloning public health relevance receptor response secretase skeletal skeletal disorder success wasting

项目摘要

DESCRIPTION (provided by applicant): Investigating the molecular etiology of disorders caused by disturbed mineral metabolism has been instrumental in identifying new circulating regulators of phosphate homeostasis, collectively referred to as 'phosphatonins.' We identified the phosphatonin 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. The FGF23 co-receptor ¿Klotho (¿KL), acting in a heteromeric complex with a canonical FGF receptor (FGFR), is required for normal phosphate metabolism. This is emphasized by the fact that ¿KL loss of function mutations lead to end organ Fgf23 resistance, and cause the phenotypic reciprocal disorder to ADHR, familial hyperphosphatemic tumoral calcinosis (TC). ¿KL is expressed as a membrane-bound protein (mKL) that mediates Fgf23-dependent signaling in target tissues, as well as a major circulating species that originates from the proteolytic cleavage of mKL within its juxta extracellular membrane domain to derive 'cKL'. The biological activity of the cKL species is unknown. The novel preliminary studies presented herein make important, mechanistic connections regarding the regulation of Fgf23 production, and significantly modify the current models explaining phosphate homeostasis. In this regard, cKL delivery to wild type mice potently stimulates bone Fgf23 mRNA production, leading to highly elevated serum Fgf23. The treated animals manifest severe hypophosphatemia, alterations in renal 1,25(OH)2 vitamin D production pathways and hyperparathyroidism, with reduced bone mineral content and fractures. Further, blood cKL concentrations in vivo are correlated with changes in phosphate metabolism, and cKL demonstrates FGFR-dependent activity. Of significance, the mice treated with cKL are biological phenocopies of a patient with an ¿Klotho gene translocation (t9:13), that resulted in markedly increased serum cKL concentrations. Collectively, these new findings demonstrate that the molecular mechanisms dictating Fgf23 production, as well as the control of Fgf23 bioactivity and expression via the ¿KL isoforms remain to be defined. Thus, the central hypothesis to be tested is: the cKL form of ¿KL controls an endocrine homeostatic axis between FGF23 target tissues and the skeleton by stimulating Fgf23 production. We expect our studies will provide novel, translational insight into rare, and common syndromes of altered FGF23 expression such as CKD-MBD, and into the basic biology of phosphate metabolism.

描述（由适用提供）：研究矿物质代谢引起的疾病的分子病因，对识别磷酸盐稳态的新的循环调节剂起着重要作用，该调节剂统称为“磷酸蛋白”。我们在位置克隆方法中鉴定了磷酸蛋白成纤维细胞生长因子23（FGF23），以隔离肾磷酸盐浪费，rick脚/骨骼/骨质分析和fracte的肾磷酸盐的特征，以隔离常染色体显性下降磷酸盐风险（ADHR）的基因。正常磷酸盐代谢需要FGF23共受体�Klotho（KL），作用于带有规范FGF受体（FGFR）的异源络合物（FGFR）。这是通过以下事实强调的：`kl功能突变的丧失导致了器官FGF23的抗性，并导致表型相互障碍对ADHR，家族性高磷酸化肿瘤钙化（TC）。 KL表示为一种膜结合的蛋白（MKL），该蛋白（MKL）介导目标时间中FGF23依赖的信号传导，以及一个主要循环系统，该物种源自其在其近处的细胞外膜结构域中MKL的蛋白水解切割，以推导'CKL'。 CKL物种的生物学活性尚不清楚。本文介绍的新的初步研究对FGF23生产的调节进行了重要的机械联系，并显着修改了当前解释磷酸盐稳态的模型。在这方面，CKL递送到野生型小鼠可能会刺激骨FGF23 mRNA产生，从而导致高度升高的血清FGF23。治疗的动物表现出严重的低磷酸血症，肾脏1,25（OH）2维生素D产生途径和甲状旁腺功能亢进症的改变，骨矿物质含量和骨折降低。此外，体内血液CKL浓度与磷酸代谢的变化相关，CKL表现出FGFR依赖性活性。重要的是，用CKL治疗的小鼠是具有klotho基因易位的患者的生物表，T9：13）导致血清CKL浓度显着升高。总的来说，这些新发现表明，分子机制决定了FGF23的产生，以及通过„ KL同工型对FGF23生物活性和表达的控制。这是：要测试的中心假设是：„ KL的CKL形式通过刺激FGF23的产生来控制FGF23目标时机和骨骼之间的内分泌稳态轴。我们预计我们的研究将提供新颖的，转化的洞察力，以了解FGF23表达（例如CKD-MBD）的罕见和常见综合症，并将其转化为磷酸代谢的基本生物学。