Elsevier

Bone

Volume 60, March 2014, Pages 87-92
Bone

Original Full Length Article
Iron and fibroblast growth factor 23 in X-linked hypophosphatemia

https://doi.org/10.1016/j.bone.2013.12.001Get rights and content

Highlights

  • Intact FGF3 is more likely to be elevated than C-terminal FGF23 in XLH.

  • Despite hypophosphatemia, C-terminal FGF23 is inversely related to iron in XLH.

  • Intact FGF23 is not related to serum iron in XLH or controls.

  • The presented data suggest that FGF23 cleavage is a regulated process even in XLH.

Abstract

Background

Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemia in autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH). Iron status influences C-terminal FGF23 (incorporating fragments plus intact FGF23) in ADHR and healthy subjects, and intact FGF23 in ADHR. We hypothesized that in XLH serum iron would inversely correlate to C-terminal FGF23, but not to intact FGF23, mirroring the relationships in normal controls.

Methods

Subjects included 25 untreated outpatients with XLH at a tertiary medical center and 158 healthy adult controls. Serum iron and plasma intact FGF23 and C-terminal FGF23 were measured in stored samples.

Results

Intact FGF23 was greater than the control mean in 100% of XLH patients, and > 2SD above the control mean in 88%, compared to 71% and 21% respectively for C-terminal FGF23. In XLH, iron correlated negatively to log-C-terminal FGF23 (r =  0.523, p < 0.01), with a steeper slope than in controls (p < 0.001). Iron was not related to log-intact FGF23 in either group. The log-ratio of intact FGF23 to C-terminal FGF23 was higher in XLH (0.00 ± 0.44) than controls (− 0.28 ± 0.21, p < 0.01), and correlated positively to serum iron (controls r = 0.276, p < 0.001; XLH r = 0.428, p < 0.05), with a steeper slope in XLH (p < 0.01).

Conclusion

Like controls, serum iron in XLH is inversely related to C-terminal FGF23 but not intact FGF23. XLH patients are more likely to have elevated intact FGF23 than C-terminal FGF23. The relationships of iron to FGF23 in XLH suggest that altered regulation of FGF23 cleaving may contribute to maintaining hypophosphatemia around an abnormal set-point.

Section snippets

Background/introduction

Under normal physiologic conditions, fibroblast growth factor 23 (FGF23) is produced by osteocytes and osteoblasts, circulates as a hormone, and binds to fibroblast growth factor receptors and the co-receptor klotho in the kidney. In the kidney, FGF23 down-regulates surface expression of sodium phosphate cotransporters (NPT2a and NPT2c), and down-regulates renal 1α-hydroxylase activity [1]. FGF23 excess is the cause of renal phosphate wasting, hypophosphatemia, and inappropriately low or normal

Study design

This was a cross-sectional analysis of samples obtained during an ongoing observational study of patients with XLH. Control subjects were included from a previously published cross-sectional sample of healthy adult subjects [5]. The purpose of this analysis was to evaluate the relationship between iron status and plasma FGF23 in XLH patients. The study was conducted in accordance with the Declaration of Helsinki and was approved by Indiana University Institutional Review Board. Written informed

FGF23 assay standard comparisons

Assay standards from the intact FGF23 assay were measured on the C-terminal FGF23 assay, and vice versa. The measurements of assay standards from each kit on the other assay provided similar numerical values for the standards in pg/ml and RU/ml (Fig. 1). For most assay standards, the ratio of intact FGF23/C-terminal FGF23 was relatively consistent between 0.8 and 1.2 across most values of FGF23 (Fig. 1C). Even using assay standards, C-terminal FGF23 (intact plus fragments) was sometimes lower

Discussion

Recently, we demonstrated that low iron concentrations were inversely related to both intact and C-terminal FGF23 concentrations in ADHR patients (with an FGF23 mutation that impaired cleavage). This provided a potential explanation for the variable age of developing the ADHR phenotype, as well as the waxing and waning of FGF23 concentrations, hypophosphatemia, and clinical symptoms observed in patients with ADHR [5]. In an ADHR mouse model FGF23 expression only became elevated during iron

Disclosures

EAI receives research funding from and is a consultant for Kyowa Hakko Kirin, Pharma Inc. MJE holds a patent on FGF23 and receives royalties from and is a consultant for Kyowa Hakko Kirin, Pharma Inc.

Acknowledgments

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging of the National Institutes of Health under Award Numbers K23AR057096, R01AR42228, P01AG18397, and KL2RR025760. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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      The XLH syndrome, like anemia-induced ADHR, is associated with elevated Fgf23 mRNA, in concert with the inability to efficiently cleave and inactivate bioactive FGF23 (Harrell et al., 1985). In a clinical study, it was reported that although mean plasma FGF23 was elevated in patients with XLH compared to normals, FGF23 correlated negatively with serum iron in both patients and normal controls (Imel et al., 2014). This study suggested that the XLH disease phenotype was not dependent upon serum iron concentrations.

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