Fibroblast growth factor 23: state of the field and future directions

Abstract

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates and is regulated by blood levels of phosphate and active vitamin D. Post-translational glycosylation by the enzyme GALNT3 and subsequent processing by furin have been demonstrated to be a regulated process that plays a role in regulating FGF23 levels. In physiologic states, FGF23 signaling is mediated by an FGF receptor and the coreceptor, Klotho. Recent work identifying a role for iron/hypoxia pathways in FGF23 physiology and their implications are discussed. Beyond its importance in primary disorders of mineral metabolism, recent work implicates FGF23 in renal disease-associated morbidity, as well as possible roles in cardiovascular disease and skeletal fragility.

Figure 1. Genomic organization, transcript profile and protein features of human FGF23

Nucleotide and amino acid sequences for the FGF23 gene (NC_000012), transcript (NM_020638) and protein (GenBank EAW88848) were obtained from the National Center for Biotechnology Information (NCBI) databases. The three exons within the FGF23 gene are marked by boxes (blue). The 5’-upstream region for the FGF23 gene is also indicated (dashed line, not to scale). The area specific for the FGF23 coding region (open reading frame region; ORF) is also marked (blue box). 5’- and 3’-untranslated regions (5’Unt and 3’Unt) are indicated. Putative O-glycosylation sites and the subtilisin proprotein convertase (SPC) protease processing site are indicated. Different epitopes within the FGF23 protein that cross react to antibodies specific for the N-terminal region (marked by blue underlines) and C-terminal region (marked by red underline) are also indicated. The proteins that are commonly identified on Western blotting and their associated molecular weights are identified as indicated.

Figure 2. FGF23 synthesis, secretion, processing, and action

A) FGF23 is produced by bone cells (primarily osteocytes and osteoblasts), circulates in the blood and acts on the kidney to induce phosphaturia, by lowering blood phosphorus levels, and inhibiting the production of the active vitamin D metabolite 1,25 (OH)₂ vitamin D₃ (1,25 D). This has the negative feedback effect of decreasing bone FGF23 production. B) FGF23 acts at renal tubule cells by binding to an FGF receptor (FGFR – most likely FGFR1) and its co-receptor Klotho to activate the mitogen-activated protein (MAP) kinase/ extracellular-signal-regulated kinases 1/2 pathway and decrease the transcription, translation and overall activity of the enzyme 25-hydroxyvitamin D₃ 1-alpha-hydroxylase (1 α hydroxylase), which converts inactive vitamin D to active 1,25-D. Receptor biding also increases phosphate transport into the urine via the sodium-dependent phosphate transporters 2a and c (NaPi2a/c). The latter action partly depends upon the coordinated activity with parathyroid hormone receptor/parathyroid related protein receptor (PTH/PTHrP-R) stimulated activity of Na/H exchange regulatory factor-1 (NHERF1), which is a PDZ domain scaffolding protein that may function to stabilize the PTH/PTHrP-R and NaPi2c in a signaling configuration via the protein kinase C/protein kinase A (PKC/PKA) pathway. C) Osteocytes and osteoblasts are the source of FGF23. In response to elevations in phosphorus and 1,25 D (and to some extent further stimulated by activation of the PTH/cAMP pathway), FGF23 transcription, translation, and secretion are stimulated. There is evidence that iron has an impact on FGF23 levels, which may be by a direct effect on bone cell FGF23 production. The mechanism by which it does, and the way in which it does, remain to be defined. D) FGF23 processing is carried out by the enzymatic activity of the enzymes polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and a subtilisin-like proprotein convertase (SPC), probably furin. The overall level of intact, biologically active FGF23 in the circulation is a reflection of the overall activity of GALNT3 and furin. In the absence of glycosylation by GALNT3, FGF23 is cleaved by furin and only the processed, N-terminal (N-term.) and C-terminal (C-term.) degradation products, which are not biologically active, are secreted. The enzyme activity of both GALNT3 and furin are regulated by cAMP. There is emerging evidence, through an as yet undefined mechanism, that iron too may be able to regulate GALNT3 and/or furin activity.

Figure 3. FGF23 in Renal Disease

A) In renal disease, very high levels of FGF23 are produced by bone cells, resulting in blood levels of FGF23 that can be up to 1,000 times greater than normal. The mechanism by which these very high levels are produced is not known. A “renal” factor possibly exists, which may or may not be produced by the kidney, and which contributes to the high levels produce in renal disease. B) In a rodent model, there is a single report that at the very high levels seen in renal failure, FGF23 has been shown to act directly on cardiac myocytes by binding to FGFR4 in a Klotho-independent manner via the phospholipase C/calcineurin pathway. C) FGF23 production by bone cells probably occurs under the stimulation of hyperphosphatemia and the administration of 1,25-D that is common in patients with renal failure. However, this alone is not enough to account for the changes that are seen, as FGF23 begins to rise even before blood phosphorus levels rise. There is even a period during which blood phosphorus levels decrease below baseline as FGF23 rises, suggesting that high phosphorus alone is not necessary the primary stimulus. All of this suggests there is physiology involved in the regulation of FGF23 that is unique to renal disease, termed here as a “renal factor.” D) It appears that virtually all the FGF23 seen in the circulation in renal failure is intact FGF23, suggesting that there is little if any processing of intact FGF23 to the C- or N-terminal products. Processing may be inhibited by hyperphosphatemia or an as yet unidentified renal factor pathway.