Control of FGF23 Bioactivity via Circulating alpha-Klotho

通过循环 α-Klotho 控制 FGF23 生物活性

• 批准号: 9012815
• 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
• 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/9012815
• 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; Tissues; Vitamin D2; Wild Type Mouse; Work; bone; bone cell; disease phenotype; extracellular; fibroblast growth factor 23; gain of function mutation; gene function; gene translocation; in vivo; inhibitor/antagonist; inorganic phosphate; insight; loss of function mutation; mortality; new therapeutic target; novel; positional cloning; receptor; response; secretase; skeletal; skeletal disorder; success; treatment response; wasting

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）：研究矿物质代谢紊乱引起的疾病的分子病因有助于确定磷酸盐稳态的新循环调节因子，统称为“磷酸素”。我们通过定位克隆方法鉴定了磷酸蛋白成纤维细胞生长因子-23 (FGF23)，以分离常染色体显性低磷血症佝偻病（ADHR）的基因，其特征是继发于肾磷酸盐消耗，佝偻病/骨软化和骨折。FGF23共受体Klotho （KL）与典型FGF受体（FGFR）以异聚物复合物的形式作用，是正常磷酸盐代谢所必需的。KL功能突变缺失导致终末器官Fgf23耐药，并导致ADHR，家族性高磷血症性肿瘤钙质沉积症（TC）的表型互反性疾病，这一事实强调了这一点。KL是一种膜结合蛋白（mKL），在靶组织中介导fgf23依赖性信号，也是一种主要的循环物种，起源于mKL在其近胞外膜结构域中的蛋白水解裂解，从而产生“cKL”。cKL的生物活性尚不清楚。本文提出的新的初步研究为Fgf23的产生提供了重要的机制联系，并显著修改了目前解释磷酸盐稳态的模型。在这方面，cKL递送给野生型小鼠可有效刺激骨Fgf23 mRNA的产生，导致血清Fgf23高度升高。治疗后的动物表现出严重的低磷血症，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，骨矿物质含量降低和骨折。此外，体内血液中cKL浓度与磷酸盐代谢变化相关，cKL表现出fgfr依赖性活性。具有重要意义的是，用cKL治疗的小鼠是患有Klotho基因易位的患者的生物学表型（9:13），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产生的分子机制，以及通过¿KL异构体控制Fgf23的生物活性和表达的机制仍有待确定。因此，需要验证的中心假设是：cKL形式的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）以及磷酸盐代谢的基础生物学提供新的、可转化的见解。