The Effects of Iron Status on FGF23 Metabolism and Bone Health.

铁状态对 FGF23 代谢和骨骼健康的影响。

• 批准号: 8095934
• 负责人: Michael J Econs
• 金额: $ 20.79万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095934
• 关键词: Affect; Age; Animal Model; Arginine; Biochemistry; Biological Assay; Blood; Bone Density; C-terminal; Calcium; Cleaved cell; Data; Diet; Dihydroxycholecalciferols; Disease; Excretory function; Familial hypophosphatemic bone disease; Ferritin; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Hemochromatosis; Homeostasis; Hormones; Hypogonadism; In Vitro; Individual; Investigation; Iron; Iron binding capacity measurement; Laboratories; Light; Measurement; Measures; Metabolism; Mus; Neck; Osteoblasts; Osteocytes; Patients; Plasma; Play; Premenopause; Production; Proteins; Questionnaires; Reporting; Role; Sampling; Serine; Serum; Testing; Urine; Vertebral column; Vitamin D; Vitamin D Nutrition; Woman; aged; bone; bone health; genome wide association study; inorganic phosphate; mRNA Expression; men; protein expression; racial difference; research study; urinary

DESCRIPTION (provided by applicant): There is a well-known connection between calcium and vitamin D nutrition and bone health. However, the connection between iron and bone health is less well established. Iron deficiency has been reported to decrease BMD in animal models and in vitro studies have demonstrated that iron deficiency affects osteoblast function. Osteoblasts and osteocytes produce the hormone FGF23, which plays a critical role in phosphate and vitamin D metabolism by increasing urinary phosphate excretion and decreasing production of 1,25 dihydroxyvitamin D. Experiments from our laboratory demonstrate that low iron concentrations are associated with high levels of FGF23 in patients with autosomal dominant hypophosphatemic rickets (ADHR). Furthermore, the increase in FGF23 concentrations is correlated with disease activity in ADHR. Preliminary data indicate that plasma FGF23 concentrations, as measured by the C-terminal assay, are also inversely correlated to serum iron concentrations in normal individuals. Data in mice also indicated that low iron diets result in marked increases in Fgf23 mRNA and protein expression, but excess intact Fgf23 is cleaved between arginine 179 and serine 180 and "inactive" fragments are secreted. Our overarching hypotheses are 1) low serum iron concentrations increase FGF23 message and protein, much of which is cleaved before secretion; 2) low iron concentrations decrease BMD and 3) genetic polymorphisms influence iron, TIBC and ferritin concentrations. We currently have bone density measurements, completed questionnaires, serum biochemistries, blood and urine samples from over 4,000 healthy premenopausal women (aged 20-45) and men (age 20-60), who were ascertained as part of ongoing studies of the genetics of bone fragility/strength. A subset of this group (1524 premenopausal white women) has been genotyped for over 500,000 SNPs. Therefore, we propose studying these previously ascertained individuals to test the above hypotheses. Successful completion of the proposed investigations will elucidate the effect of iron status on FGF23 metabolism and bone density in normal individuals, provide an understanding of racial differences in phosphate homeostasis, and identify genetic factors affecting iron status. PUBLIC HEALTH RELEVANCE: The goals of this application are to elucidate the effect of iron status on FGF23 metabolism and bone density in normal individuals, understand racial differences in phosphate homeostasis, and to perform a genome wide association study to identify genetic factors that affect iron status.

描述（由申请人提供）：钙和维生素D营养与骨骼健康之间存在众所周知的联系。但是，铁与骨骼健康之间的联系还不太确定。据报道，铁缺乏症可以降低动物模型中的BMD，体外研究表明铁缺乏会影响成骨细胞功能。成骨细胞和骨细胞产生激素FGF23，通过增加尿磷酸盐排泄并降低1,25二羟基毒素D的产生，在磷酸盐和维生素D代谢中起着至关重要的作用。瑞克（ADHR）。此外，FGF23浓度的增加与ADHR中的疾病活性相关。初步数据表明，通过C末端测定测量的血浆FGF23浓度也与正常个体的血清铁浓度成反比。小鼠的数据还表明，低铁饮食会导致FGF23 mRNA和蛋白质表达显着增加，但是多余的FGF23在精氨酸179和丝氨酸180之间裂解，而“无效”片段被分泌。我们的总体假设是1）低血清铁浓度会增加FGF23信息和蛋白质，其中大部分在分泌前裂解。 2）低铁浓度降低BMD，3）遗传多态性会影响铁，TIBC和铁蛋白浓度。目前，我们进行了骨密度测量，完成的问卷，血清生物学，血液和尿液样本，来自4,000多名健康的绝经前女性（20-45岁）和男性（20-60岁），这些妇女（20-60岁）被确定为骨骼脆弱/强度遗传学的持续研究的一部分。该组的一部分（1524名绝经前白人妇女）的基因分型为500,000多个SNP。因此，我们建议研究这些先前确定的个体以检验上述假设。 成功完成拟议的研究将阐明铁状态对正常个体中FGF23代谢和骨密度的影响，提供对磷酸盐稳态中种族差异的理解，并确定影响铁状态的遗传因素。 公共卫生相关性：本应用的目标是阐明铁状态对正常个体中FGF23代谢和骨密度的影响，了解磷酸盐稳态的种族差异，并进行基因组广泛的关联研究，以识别影响铁状态的遗传因素。