Regulation of Fibroblast Growth Factor 23 by Iron, EPO, and HIF

Abstract

Purpose of review: Fibroblast growth factor-23 (FGF23) is the key hormone produced in bone critical for phosphate homeostasis. Elevated serum phosphorus and 1,25dihydroxyvitaminD stimulates FGF23 production to promote renal phosphate excretion and decrease 1,25dihydroxyvitaminD synthesis. Thus completing the feedback loop and suppressing FGF23. Unexpectedly, studies of common and rare heritable disorders of phosphate handling identified links between iron and FGF23 demonstrating novel regulation outside the phosphate pathway. Recent Findings: Iron deficiency combined with an FGF23 cleavage mutation was found to induce the autosomal dominant hypophosphatemic rickets phenotype. Physiological responses to iron deficiency, such as erythropoietin production as well as hypoxia inducible factor activation, have been indicated in regulating FGF23. Additionally, specific iron formulations, used to treat iron deficiency, alter post-translational processing thereby shifting FGF23 protein secretion. Summary: Molecular and clinical studies revealed that iron deficiency, through several mechanisms, alters FGF23 at the transcriptional and post-translational level. This review will focus upon the novel discoveries elucidated between iron, its regulators, and their influence on FGF23 bioactivity.

Integrated Hypoxia Signaling and Oxidative Stress in Developmental Neurotoxicity of Benzo[a]Pyrene in Zebrafish Embryos

“…The expression levels were quantified and the results confirmed that B[a]P was able to dose-dependently reduce the expression ( Figure 6 M). We also detected another Hif target gene, epo ( Figure 6 G–L), which is expressed in brain during embryogenesis and is functionally associated with neural differentiation and proliferation [ 38 , 39 , 40 ]. The quantitative results indicated that the expression of epo was also dose-dependently reduced by B[a]P treatment ( Figure 6 N), and the effect sizes at each dose were similar to those for hif2a in B[a] P- treated embryos.…”

FGF/FGFR signaling in health and disease

“… 23 For example, the tissue-specific alternative splicing in D3 of FGFR1, FGFR2, and FGFR3 can generate b and c isoforms, and thus determines the binding specificity/promiscuity for individual FGFs at diverse cells and tissues. 24 Furthermore, it is well documented that epigenetic mechanisms, 25 the posttranslational modifications, such as phosphorylation, 26 glycosylation, 27 ubiquitination, 28 and cellular trafficking of FGFs/FGFRs 29 , 30 are also involved in the regulation of the expressions of FGF/FGFR signaling components and the signal specificity, intensity, and timing.…”

Perspectives for the therapy of anemia of chronic diseases

“…Another potential threat is that HIF stabilization may be associated with an increase in circulating fibroblast growth factor 23 (FGF23) level, and high concentrations of FGF23 have been associated with cardiovascular complications and bone mineralization disorders. However, the increase in FGF23 caused by HIF-PHI is lower than its increase after administration of ESAs [69,70].…”