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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (03))
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Robinson-Cohen, Cassianne; Bartz, Traci M; Lai, Dongbing et al. (2018) Genetic Variants Associated with Circulating Fibroblast Growth Factor 23. J Am Soc Nephrol 29:2583-2592
Econs, Michael J (2017) Genetic diseases resulting from disordered FGF23/klotho biology. Bone 100:56-61
Koller, Daniel L; Imel, Erik A; Lai, Dongbing et al. (2016) Genome-wide association study of serum iron phenotypes in premenopausal women of European descent. Blood Cells Mol Dis 57:50-3
Imel, Erik A; Liu, Ziyue; McQueen, Amie K et al. (2016) Serum fibroblast growth factor 23, serum iron and bone mineral density in premenopausal women. Bone 86:98-105
Econs, Michael J (2015) Conventional Therapy in Adults With XLH Improves Dental Manifestations, But Not Enthesopathy. J Clin Endocrinol Metab 100:3622-4
Imel, Erik A; Peacock, Munro; Gray, Amie K et al. (2011) Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab 96:3541-9
Yamazaki, Yuji; Imura, Akihiro; Urakawa, Itaru et al. (2010) Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun 398:513-8
Ichikawa, Shoji; Koller, Daniel L; Curry, Leah R et al. (2009) Association of adenylate cyclase 10 (ADCY10) polymorphisms and bone mineral density in healthy adults. Calcif Tissue Int 84:97-102