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

描述（由申请人提供）：众所周知，钙和维生素D营养与骨骼健康之间存在联系。然而，铁和骨骼健康之间的联系还没有得到很好的证实。据报道，在动物模型中缺铁会降低骨密度，体外研究表明缺铁会影响成骨细胞的功能。成骨细胞和骨细胞产生激素FGF23，通过增加尿磷酸盐排泄和减少1,25二羟基维生素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，在常染色体显性低磷血症佝偻病（ADHR）患者中，低铁浓度与高水平的FGF23相关。此外，FGF23浓度的升高与ADHR的疾病活动性相关。初步数据表明，血浆FGF23浓度，通过c端测定，也与正常人血清铁浓度呈负相关。小鼠的数据还表明，低铁饮食导致Fgf23 mRNA和蛋白表达显著增加，但过量的完整Fgf23在精氨酸179和丝氨酸180之间断裂，分泌“非活性”片段。我们的主要假设是：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被切割；2)低铁浓度降低骨密度；3)遗传多态性影响铁、TIBC和铁蛋白浓度。我们目前有超过4000名健康的绝经前女性（20-45岁）和男性（20-60岁）的骨密度测量、完成的问卷、血清生化、血液和尿液样本，这些样本被确定为正在进行的骨骼脆弱性/强度遗传学研究的一部分。该组的一个子集（1524名绝经前白人妇女）已被基因分型超过500,000个snp。因此，我们建议研究这些先前确定的个体来检验上述假设。成功完成所提出的研究将阐明正常个体中铁状态对FGF23代谢和骨密度的影响，为磷酸盐稳态的种族差异提供理解，并确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.