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

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。然而，铁和骨骼健康之间的联系还不太明确。据报道，缺铁会降低动物模型中的BMD，体外研究表明缺铁会影响成骨细胞功能。成骨细胞和骨细胞产生激素FGF 23，其通过增加尿磷酸盐排泄和减少1，25二羟维生素D的产生在磷酸盐和维生素D代谢中起关键作用。我们实验室的实验表明，低铁浓度与常染色体显性遗传性低磷血症性佝偻病（ADHR）患者的高水平FGF 23相关。此外，FGF 23浓度的增加与ADHR中的疾病活动相关。初步数据表明，血浆FGF23浓度，如通过C-末端测定，也呈负相关，血清铁浓度在正常个体。小鼠中的数据还表明，低铁饮食导致Fgf23 mRNA和蛋白质表达显著增加，但过量的完整Fgf23在精氨酸179和丝氨酸180之间被切割，并分泌"无活性"片段。我们的首要假设是1）低血清铁浓度增加FGF 23信息和蛋白，其中大部分在分泌前被切割; 2）低铁浓度降低BMD和3）遗传多态性影响铁，TIBC和铁蛋白浓度。我们目前有来自4,000多名健康绝经前女性（年龄20 - 45岁）和男性（年龄20 - 60岁）的骨密度测量、完成的问卷调查、血清生化、血液和尿液样本，这些样本是作为正在进行的骨脆性/强度遗传学研究的一部分而确定的。这一组的一个亚组（1524名绝经前白色妇女）已被基因分型为超过500，000个SNP。因此，我们建议研究这些先前确定的个体来验证上述假设。 成功完成拟议的调查将阐明铁状态对正常个体FGF 23代谢和骨密度的影响，了解磷酸盐稳态的种族差异，并确定影响铁状态的遗传因素。 公共卫生相关性：本申请的目的是阐明铁状态对正常个体中FGF 23代谢和骨密度的影响，了解磷酸盐稳态的种族差异，并进行全基因组关联研究以鉴定影响铁状态的遗传因素。

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.