Control of FGF23 Bioactivity via Circulating alpha-Klotho

通过循环 α-Klotho 控制 FGF23 生物活性

• 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
• 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

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）：研究由矿物质代谢紊乱引起的疾病的分子病因学有助于鉴定磷酸盐稳态的新循环调节剂，统称为“磷酸酶”。“我们在定位克隆方法中鉴定了磷酸化成纤维细胞生长因子-23（FGF 23），以分离常染色体显性低磷酸盐血症性佝偻病（ADHR）的基因，其特征在于继发于肾磷酸盐消耗、佝偻病/骨软化和骨折的低磷酸盐血症。FGF 23辅助受体<$Klotho（<$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。这一点通过以下事实强调：KL功能丧失突变导致终末器官Fgf 23抗性，并导致ADHR表型相互失调，家族性高磷酸盐血症肿瘤性钙质沉着症（TC）。KL表达为介导靶组织中Fgf 23依赖性信号传导的膜结合蛋白（mKL），以及源自mKL在其胞外膜结构域内的蛋白水解裂解以衍生“cKL”的主要循环物质。cKL物质的生物活性未知。 本文提出的新的初步研究，使重要的，机制的联系，关于Fgf 23生产的调节，并显着修改目前的模型解释磷酸盐稳态。在这方面，cKL递送至野生型小鼠有效地刺激骨Fgf 23 mRNA产生，导致血清Fgf 23高度升高。治疗的动物表现出严重的低磷酸盐血症，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cKL浓度与磷酸盐代谢的变化相关，并且cKL表现出FGFR依赖性活性。具有重要意义的是，用cKL处理的小鼠是具有<$Klotho基因易位（t9：13）的患者的生物学表型，其导致血清cKL浓度显著增加。总的来说，这些新的发现表明，决定Fgf 23生产的分子机制，以及通过KL亚型控制Fgf 23生物活性和表达仍有待确定。因此，要检验的中心假设是：cKL形式的KL通过刺激Fgf 23的产生来控制FGF 23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提供新的，翻译洞察罕见的，常见的综合征改变FGF 23的表达，如CKD-MBD，并进入磷酸盐代谢的基础生物学。