Upstream Regulators of Fibroblast Growth Factor 23

Abstract

Fibroblast growth factor 23 (FGF23) has been described as an important regulator of mineral homeostasis, but has lately also been linked to iron deficiency, inflammation, and erythropoiesis. FGF23 is essential for the maintenance of phosphate homeostasis in the body and activating mutations in the gene itself or inactivating mutations in its upstream regulators can result in severe chronic hypophosphatemia, where an unbalanced mineral homeostasis often leads to rickets in children and osteomalacia in adults. FGF23 can be regulated by changes in transcriptional activity or by changes at the post-translational level. The balance between O-glycosylation and phosphorylation is an important determinant of how much active intact or inactive cleaved FGF23 will be released in the circulation. In the past years, it has become evident that iron deficiency and inflammation regulate FGF23 in a way that is not associated with its classical role in mineral metabolism. These conditions will not only result in an upregulation of FGF23 transcription, but also in increased cleavage, leaving the levels of active intact FGF23 unchanged. The exact mechanisms behind and function of this process are still unclear. However, a deeper understanding of FGF23 regulation in both the classical and non-classical way is important to develop better treatment options for diseases associated with disturbed FGF23 biology. In this review, we describe how the currently known upstream regulators of FGF23 change FGF23 transcription and affect its post-translational modifications at the molecular level.

Keywords: FGF23; erythropoiesis; hypoxia; inflammation; iron deficiency; osteocytes; phosphate; vitamin D.

Figure 1

FGF23 processing. The premature FGF23 protein is a 251-amino acid long glycoprotein. In order to form the mature form of FGF23 the first 25 amino acids are removed through cleavage. FGF23 can be O-glycosylated at Thr¹⁷⁸, which protects it from cleavage and results in active FGF23 in the circulation. The alternative is for FGF23 to be phosphorylated at Ser¹⁸⁰. This results in cleavage at the consensus sequence (Arg¹⁷⁶-X-X-Arg¹⁷⁹) and inactive cleaved FGF23 in the circulation.

Figure 2

Schematic overview of classical FGF23 regulation. cKL binds to the FGFR1 and activates FGF23 transcription via the MAPK pathway. 1,25(OH)2D3 binds to the VDR, which heterodimerizes with the RXRs and can bind to the VDRE in the FGF23 promotor. PTH binds to the PTHR1 on the cell membrane, and activates the cAMP/PKA pathway. This has two effects: 1) NURR1 mRNA increases, resulting in increased FGF23 transcription; 2) inhibition of SOST, thereby indirectly stimulating FGF23 transcription by releasing the suppression of the WNT pathway. Both Ca²⁺ and Pi can activate FGF23 transcription independently. Ca²⁺ enters the cell via a Ca²⁺ transporter. In the cells it inhibits DMP1, an inhibitor of the NFAT1 pathway, thus activating the NFAT pathway, leading to FGF23 transcription stimulation. Phosphate enters the cells through phosphate transporters. In the cell it stimulates FGF23 through the production of ROS through a yet unknown mechanism. Furthermore, it increases expression of GalNT3, resulting in protection from cleavage of the full-length FGF23 protein. Also, CCPs can increase FGF23 transcription but the mechanism remains unknown. Lastly, PHEX is able to inhibit FGF23 transcription through a yet unknown mechanism and interact with PC2 to increase FGF23 cleavage. 1,25D, 1,25-dihydroxyvitamin D₃; Ca²⁺, calcium; cAMP, Cyclic adenosine 3′,5′-monophosphate; CCP, calciprotein particles; cFGF23, cleaved fibroblast growth factor 23; cKL, cleaved klotho; DMP1, dentin matrix protein 1; iFGF23, intact fibroblast growth factor 23; FGFR1, fibroblast growth receptor 1; GalNt3, polypeptide N-acetylgalactosaminyltransferase 3; MAPK, mitogen-activated protein kinase; NADPH, nicotinamide adenine dinucleotide phosphate; NFAT, nuclear factor of activated T cells; Nurr1, nuclear receptor related-1 protein; PC2, proprotein convertase; PHEX, phosphate regulating endopeptidase homolog X-linked; Pi, phosphate; PKA, protein kinase A; PTH, parathyroid hormone; PTHR1, parathyroid hormone receptor 1; ROS, reactive oxygen species; RXR, retinoid X receptor; SOST, sclerostin; VDR, vitamin D receptor.

Figure 3

Schematic overview of non-classical FGF23 regulation. Hypoxia, iron deficiency, and inflammation all result in Hif1α stabilization. Hif1α, which can be stimulated by inflammation, binds to the HRE in the FGF23 promotor and stimulate expression. Hif1α can also indirectly regulate FGF23: 1) it stimulates EPO, which directly stimulates FGF23 transcription and 2) it inhibits GalNt3, resulting in increased FGF23 cleavage. Insulin is able to inhibit FGF23 transcription through the Pi3K/Akt pathway, while leptin stimulates FGF23 transcription through a yet unknown mechanism. cFGF23, cleaved fibroblast growth factor 23; EPO, erythropoietin; iFGF23, intact fibroblast growth factor 23; GalNt3, polypeptide N-acetylgalactosaminyltransferase 3; HIF1α, hypoxia inducible factor 1 α; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B.