Dietary and hormonal regulation of FGF-23 in humans

描述(由申请人提供)： 磷酸盐(PO4)对骨骼矿化、肌肉功能、信号转导以及能量的产生和利用都是必不可少的。PO4的异常处理表现为低磷性软骨病和慢性肾功能衰竭，并由此导致甲状旁腺增生和骨营养不良。来自三种磷酸消耗疾病(X连锁低磷血症、常染色体显性遗传性低磷血症和肿瘤骨软化症)的数据表明，成纤维细胞生长因子23(FGF-23)是一种新的磷酸尿激素，导致这些罕见患者的严重磷酸盐消耗。本提案的主要目的是描述成纤维细胞生长因子-23在正常P04生理过程中的作用以及调节成纤维细胞生长因子-23的因素。在每一个方案中，我们都将检测成纤维细胞生长因子-23、血和尿PO4，以及其他已知影响PO4的激素，如甲状旁腺激素(PTH)和1，25-二羟基维生素D。我们假设，通过协方差分析测量的成纤维细胞生长因子-23的日变化将与血PO4和肾PO4的清除量平行，而不同于PTH。在特定的目标2中，100名维生素D缺乏的健康受试者被随机分配到钙剂500 mg，每日2次或钙剂500 mg，每日2次+维生素D 50,000单位，每日1次，为期12周，以确定在控制了血PO4和PTH的变化后，维生素D是否会增加成纤维细胞生长因子-23的水平。为了确定甲状旁腺激素抑制对成纤维细胞生长因子-23的影响，在特定的目标3中，44名健康受试者被随机分配到安慰剂或拟钙剂，Cinacalcet 30 mg，qd(它降低甲状旁腺素水平)，并同时加载磷酸盐，以确定P04负荷是否独立于甲状旁腺素增加成纤维细胞生长因子-23水平。最后，为了确定甲状旁腺素刺激对成纤维细胞生长因子-23的影响，在特定的目标4中，我们将测定58名健康男性的成纤维细胞生长因子-23，这些人以0.55U/kg/小时的剂量输注人甲状旁腺素(1-34)，以确定甲状旁腺素是否对人成纤维细胞生长因子-23有直接影响。综上所述，在几种罕见的疾病中，成纤维细胞生长因子-23负责磷酸盐的消耗，并且似乎在正常的磷酸盐生理中起着至关重要的作用。这项建议中的研究将促进我们对成纤维细胞生长因子-23在人类中的激素调节的理解，并可能有助于开发新的治疗低磷血症或高磷血症患者的方法。

DESCRIPTION (provided by applicant): Phosphate (PO4) is essential for bone mineralization, muscle function, signal transduction and the creation and utilization of energy. Abnormal PO4 handling occurs in forms of hypophosphatemic rickets, and in chronic renal failure with resultant parathyroid hyperplasia and osteodystrophy. Data from three PO4 wasting disorders (X-linked hypophosphatemia, autosomal dominant hypophosphatemic rickets, and tumor induced osteomalacia) demonstrate that fibroblast growth factor 23 (FGF-23) is a novel phosphaturic hormone that is responsible for severe phosphate wasting in these rare patients. The overarching goal of this proposal is to describe the role of FGF-23 in normal P04 physiology and factors that regulate FGF-23. In each of these protocols, we will measure FGF-23, blood and urinary PO4, and other hormones known to affect PO4, like parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D. In Specific Aim 1, 20 healthy subjects will consume a research diet, and undergo 24 hour blood and urine frequent sampling to assess the diurnal variation in FGF-23. We hypothesize that the diurnal variation in FGF-23, as measured by cosinor analysis, will parallel that of blood PO4 and the renal clearance of PO4, and differ from that of PTH. In Specific Aim 2, 100 healthy vitamin D-deficient subjects will be randomly assigned to calcium 500 mg BID or calcium 500 mg BID plus vitamin D 50,000 units Q WK for 12 weeks to determine whether vitamin D increases FGF-23 levels after controlling for changes in blood PO4 and PTH. To determine the effects of PTH suppression on FGF-23, in Specific Aim 3, 44 healthy subjects will be randomly assigned to either placebo or a calcimimetic, Cinacalcet 30 mg QD (which lowers PTH levels), and concurrently phosphate loaded to determine whether P04 loading increases FGF-23 levels independently of PTH. Finally, to determine effect of PTH stimulation on FGF-23, in Specific Aim 4, we will measure FGF-23 in 58 healthy men who were infused with human PTH(1-34) at a dose of 0.55 U/kg/hr to determine whether PTH has a direct effect on FGF-23 in humans. To summarize, FGF-23 is responsible for phosphate wasting in several rare disorders and appears to play a vital role in normal phosphate physiology. The studies in this proposal will advance our understanding of the hormonal regulation of FGF-23 in humans and may help in the development of novel treatments for patients with hypo- or hyperphosphatemic disorders.