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：
8503007
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/8503007
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（由申请人提供）：调查矿物质代谢紊乱引起的疾病的分子病因学有助于确定磷酸盐稳态的新循环调节剂，统称为“磷酸钙”。我们鉴定了磷酸钙蛋白成纤维细胞生长因子 23 (FGF23)采用定位克隆方法分离常染色体显性低磷血症性佝偻病 (ADHR) 基因，其特征是继发于肾脏的低磷血症磷酸盐消耗、佝偻病/骨软化症和骨折。 Klotho (¿KL) 与典型 FGF 受体 (FGFR) 形成异聚复合物，是正常磷酸盐代谢所必需的，这一事实强调了 ¿ KL功能缺失突变导致终末器官Fgf23抵抗，并导致ADHR、家族性高磷酸盐肿瘤性钙质沉着症(TC)的表型相互紊乱。 KL 表达为膜结合蛋白 (mKL)，在靶组织中介导 Fgf23 依赖性信号传导，也是一种主要循环物种，源自 mKL 在其邻近细胞外膜结构域内的蛋白水解裂解，衍生出“cKL”。 cKL 物种的活性尚不清楚，本文提出的新颖初步研究在 Fgf23 产生的调节方面建立了重要的机制联系，并显着修改了解释磷酸盐的当前模型。在这方面，将 cKL 递送至野生型小鼠可有效刺激骨 Fgf23 mRNA 的产生，导致接受治疗的动物出现严重的低磷血症、肾脏 1,25(OH)2 维生素 D 产生途径的改变和甲状旁腺功能亢进。此外，体内血液 cKL 浓度与磷酸盐代谢的变化相关，并且 cKL 表现出重要的 FGFR 依赖性活性。使用 cKL 治疗的患者是患有 ¿ Klotho 基因易位 (t9:13)，导致血清 cKL 浓度显着增加。总的来说，这些新发现表明，决定 Fgf23 产生以及通过 ¿ 控制 Fgf23 生物活性和表达的分子机制。 KL 同工型仍有待定义，因此，要检验的中心假设是： ¿ 的 cKL 形式。 KL 通过刺激 FGF23 的产生来控制 FGF23 靶组织和骨骼之间的内分泌稳态轴，我们希望我们的研究将为罕见和常见的 FGF23 表达改变综合征（如 CKD-MBD）和基础生物学提供新的转化见解。磷酸盐代谢。