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Review
. 2019 Aug 27;20(17):4195.
doi: 10.3390/ijms20174195.

The Role of Fibroblast Growth Factor 23 in Inflammation and Anemia

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Free PMC article
Review

The Role of Fibroblast Growth Factor 23 in Inflammation and Anemia

Brian Czaya et al. Int J Mol Sci. .
Free PMC article

Abstract

In patients with chronic kidney disease (CKD), adverse outcomes such as systemic inflammation and anemia are contributing pathologies which increase the risks for cardiovascular mortality. Amongst these complications, abnormalities in mineral metabolism and the metabolic milieu are associated with chronic inflammation and iron dysregulation, and fibroblast growth factor 23 (FGF23) is a risk factor in this context. FGF23 is a bone-derived hormone that is essential for regulating vitamin D and phosphate homeostasis. In the early stages of CKD, serum FGF23 levels rise 1000-fold above normal values in an attempt to maintain normal phosphate levels. Despite this compensatory action, clinical CKD studies have demonstrated powerful and dose-dependent associations between FGF23 levels and higher risks for mortality. A prospective pathomechanism coupling elevated serum FGF23 levels with CKD-associated anemia and cardiovascular injury is its strong association with chronic inflammation. In this review, we will examine the current experimental and clinical evidence regarding the role of FGF23 in renal physiology as well as in the pathophysiology of CKD with an emphasis on chronic inflammation and anemia.

Keywords: anemia; chronic kidney disease (CKD); erythropoietin (EPO); fibroblast growth factor 23 (FGF23); fibroblast growth factor receptor (FGFR); hepcidin; inflammation; klotho; phosphate.

Conflict of interest statement

C.F. received financial research support from Bayer and Amgen and is a scientific advisor for Calico. B.C. declares no conflict of interest.

Figures

Figure 1
Figure 1
Fibroblast growth factor 23 (FGF23) regulation by post-translational modification. As a full-length biologically active peptide in circulation, FGF23 is O-glycosylated by GalNT3 at several residues such as Thr178, which protects FGF23 from proteolytic cleavage by pro-protein convertases such as furin. Vice versa, as proteolytic cleaved fragments in circulation, FAM20C phosphorylates FGF23 at multiple amino acids, such as Ser180. This phosphorylation event impedes O-glycosylation by GalNT3 and allows furin to recognize its Arg176-His177-Thr178-Arg179-Ser180 consensus sequence in FGF23, thus leading to FGF23 cleavage and separation of the N-terminal and C-terminal fragments. GalNT3, polypeptide N-acetylgalactosaminyltransferase 3; FAM20C, secretory protein kinase family with sequence similarity-20 member C; Arg, arginine; His, histidine; Thr, threonine; Ser, serine.
Figure 2
Figure 2
Canonical and non-canonical signaling of FGF23. Canonical FGF23-mediated signaling occurs in an αKlotho-dependent manner in the kidney and parathyroid, leading to the phosphorylation of FRS2α and MAPK. Activation of this signaling pathway results in the downregulation of the sodium-dependent phosphate co-transporters, NaPi-2A and NaPi-2c, on the apical surface of the proximal tubule. In the parathyroid, canonical signaling results in Egr-1 activation and suppression of PTH production. Non-canonical FGF23-mediated signaling occurs in an αKlotho-independent manner in cell types such as myocytes, hepatocytes and neutrophils. In myocytes and hepatocytes, FGF23 binds FGFR4 to activate the PLCγ/calcineurin/NFAT pathway, leading to the induction of gene programs involved in cardiac remodeling and production of pro-inflammatory cytokines. In neutrophils, FGF23 binds FGFR2 which leads to the activation of PKA and subsequent inhibition of the GTPase, Rap1. As a result, β2-integrin deactivation occurs on the cell surface and leads to impaired leukocyte recruitment and host defense. FRS2α, FGF receptor substrate 2α; MAPK, Ras/mitogen-activated protein kinase; Egr-1, early growth-responsive 1; PTH, parathyroid hormone; PLCγ; phospholipase Cγ; NFAT, nuclear factor of activated T-cells; PKA, protein kinase A; Rap1, Ras-proximate-1.
Figure 3
Figure 3
A vicious cycle connecting FGF23 and chronic inflammation. Pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β are potent inducers of FGF23 production. As a consequence of these factors promoting the uncontrolled production of FGF23, excess levels of FGF23 in circulation elevate the production of various cytokines in diverse tissues, which in turn, amplifies systemic inflammation. The establishment of this vicious cycle contributes to widespread tissue injury and the acceleration of CKD. TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; IL-1β, interleukin-1β; CKD, chronic kidney disease.
Figure 4
Figure 4
The pleotropic actions of FGF23 in anemia. As a direct consequence, FGF23 reduces the secretion of EPO from the kidney, thereby decreasing the differentiation of erythroid progenitors, such as pro-erythroblasts, to mature erythrocytes. In addition, FGF23 directly reduces the fraction of erythrocytes in the G2/M phase of their cell cycle and enhances erythrocyte apoptosis. As an indirect consequence, FGF23 enhances the inflammatory milieu, which in turn, promotes hepcidin excess and leads to the restriction of iron for erythropoiesis. EPO, erythropoietin; EPOR, erythropoietin receptor.

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