Fibroblast Growth Factor 23: Mineral Metabolism and Beyond

Grabner, Alexander; Mazzaferro, Sandro; Cianciolo, Giuseppe; Krick, Stefanie; Capelli, Irene; Rotondi, Silverio; Ronco, Claudio; Manna, Gaetano La; Faul, Christian

doi:10.1159/000468952

Cited by 33 publications

(26 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the interplay between GALNT3 and FAM20C activity within the endoplasmic reticulum and golgi network dictates the secreted form of FGF23. Importantly, highly elevated serum FGF23 levels have been found to induce detrimental offtarget effects in tissues outside of kidney (29,30). Recent studies have identified factors regulating FGF23 not involved in the phosphate and 1,25D feedback network (31,32).…”

Section: Introductionmentioning

confidence: 99%

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

Wheeler

Clinkenbeard

2019

Curr Mol Bio Rep

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Wheeler

Clinkenbeard

2019

Curr Mol Bio Rep

View full text Add to dashboard Cite

show abstract

“…FGF23 plasma levels are increased in parallel to progression of CKD and are regarded as the today earliest indicator for derangements in phosphate homeostasis [ 6 ]. In addition, FGF23 serum levels are identified as an independent risk factor for end-stage renal disease and cardiovascular mortality in CKD patients [ 7 , 8 ]. Faul and colleagues have shown in a mouse model that FGF23 application results in myocardial hypertrophy [ 9 ], a finding that might be driven by FGF23 binding at the FGF receptor 4 (FGFR4) on myocardial tissue [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase

et al. 2017

View full text Add to dashboard Cite

Plasma levels of FGF23 are increased in patients with chronic kidney disease. Beside its role in phosphate homeostasis, iron deficiency and anemia are associated with increased FGF23 plasma levels. Recently, FGF23 plasma levels were shown to be increased in mice after treatment with hypoxia inducible factor-proline hydroxylase (HIF-PH) inhibitors which are strong inducers of erythropoietin and erythropoiesis and are known to modulate iron uptake and availability. Therefore we investigated a potential context between expression of FGF23 and stimulation of erythropoiesis using a HIF-PH inhibitor and erythropoietin in rats. FGF23 plasma levels are induced at peak levels 2 h after intravenous injection of recombinant human Erythropoietin (rhEPO). Likewise induction of endogenous EPO using a HIF-PH inhibitor (BAY 85–3934) is followed by an increase of FGF23 plasma levels. In contrast to rhEPO the HIF-PH inhibitor induces lower peak levels of FGF23 applying equivalent hematopoietic doses. Bone and bone marrow were identified as sources of EPO-induced FGF23. Immediate induction of FGF23 mRNA was also detected in EPO receptor positive murine hematopoietic BAF3 cells after treatment with rhEPO but not after treatment with the HIF-PH inhibitor. Pretreatment of mice with a neutralizing anti-EPO antibody abrogated FGF23 induction by the HIF-PH inhibitor. Thus, direct impact on FGF23 expression by HIF-PH inhibition in vivo via hypoxia mimicking and modulation of iron metabolism appears unlikely. Collectively, the findings point to an EPO dependent regulation pathway of FGF23 gene expression which might be important in the context of erythropoiesis stimulating therapies in patients with renal anemia.

show abstract

“…FGF23 has been characterized as a hormonal regulator of circulating phosphate and vitamin D levels as well as a prognostic risk factor for cardiovascular mortality in patients with chronic kidney disease ( 28 , 34 – 36 ). The role of FGF23 role as an inflammatory facilitator has also been recently studied ( 5 , 37 , 38 ). Interestingly, it may be involved in several metabolic processes, including glucose and fat metabolism.…”

Section: Discussionmentioning

confidence: 99%

FGF23 Induction of O-Linked N-Acetylglucosamine Regulates IL-6 Secretion in Human Bronchial Epithelial Cells

et al. 2018

Self Cite

View full text Add to dashboard Cite

The hexosamine biosynthetic pathway (HBP) generates the substrate for the O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins. The HBP also serves as a stress sensor and has been reported to be involved with nuclear factor of activated T-cells (NFAT) activation, which can contribute to multiple cellular processes including cell metabolism, proliferation, and inflammation. In our previously published report, Fibroblast Growth Factor (FGF) 23, an important endocrine pro-inflammatory mediator, was shown to activate the FGFR4/phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling in chronic inflammatory airway diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Here, we demonstrate that FGF23 increased the O-GlcNAc modification of proteins in HBECs. Furthermore, the increase in O-GlcNAc levels by FGF23 stimulation resulted in the downstream activation of NFAT and secretion of interleukin-6 (IL-6). Conversely, inhibition of FGF23 signaling and/or O-GlcNAc transferase (OGT)/O-GlcNAc reversed these effects. Collectively, these data suggest that FGF23 induced IL-6 upregulation and secretion is, at least, partially mediated via the activation of the HBP and O-GlcNAc levels in HBECs. These findings identify a novel link whereby FGF23 and the augmentation of O-GlcNAc levels regulate airway inflammation through NFAT activation and IL-6 upregulation in HBECs. The crosstalk between these signaling pathways may contribute to the pathogenesis of chronic inflammatory airway diseases such as COPD and CF as well as metabolic syndromes, including diabetes.

show abstract

Fibroblast Growth Factor 23: Mineral Metabolism and Beyond

Cited by 33 publications

References 38 publications

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

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

FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase

FGF23 Induction of O-Linked N-Acetylglucosamine Regulates IL-6 Secretion in Human Bronchial Epithelial Cells

Contact Info

Product

Resources

About