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Review
. 2021 Feb;66(2):R23-R32.
doi: 10.1530/JME-20-0178.

FGF23 signalling and physiology

Bryan B Ho  1 , Clemens Bergwitz  1
Affiliations
Review

FGF23 signalling and physiology

Bryan B Ho et al. J Mol Endocrinol. 2021 Feb.

Abstract

Fibroblast growth factor 23 (FGF23) is a phosphotropic hormone that belongs to a subfamily of endocrine FGFs with evolutionarily conserved functions in worms and fruit flies. FAM20C phosphorylates FGF23 post-translationally, targeting it to proteolysis through subtilisin-like proprotein convertase FURIN, resulting in secretion of FGF23 fragments. O-glycosylation of FGF23 through GALNT3 appears to prevent proteolysis, resulting in secretion of biologically active intact FGF23. In the circulation, FGF23 may undergo further processing by plasminogen activators. Crystal structures show that the ectodomain of the cognate FGF23 receptor FGFR1c binds with the ectodomain of the co-receptor alpha-KLOTHO. The KLOTHO-FGFR1c double heterodimer creates a high-affinity binding site for the FGF23 C-terminus. The topology of FGF23 deviates from that of paracrine FGFs, resulting in poor affinity for heparan sulphate, which may explain why FGF23 diffuses freely in the bone matrix to enter the bloodstream following its secretion by cells of osteoblastic lineage. Intact FGF23 signalling by this canonical pathway activates FRS2/RAS/RAF/MEK/ERK1/2. It reduces serum phosphate by inhibiting 1,25-dihydroxyvitamin D synthesis, suppressing intestinal phosphate absorption, and by downregulating the transporters NPT2a and NPT2c, suppressing phosphate reabsorption in the proximal tubules. The physiological role of FGF23 fragments, which may be inhibitory, remains unclear. Pharmacological and genetic activation of canonical FGF23 signalling causes hypophosphatemic disorders, while its inhibition results in hyperphosphatemic disorders. Non-canonical FGF23 signalling through binding and activation of FGFR3/FGFR4/calcineurin/NFAT in an alpha-KLOTHO-independent fashion mainly occurs at extremely elevated circulating FGF23 levels and may contribute to mortality due to cardiovascular disease and left ventricular hypertrophy in chronic kidney disease.

Keywords: CKD; FGF receptor; FGF23; KLOTHO; PTH; erythropoetin; hematopoesis; iron; mineralisation; phosphate homeostasis; phosphate signalling.

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Conflict of interest statement

Conflicts of Interest/Disclosures

B.B.H. declares to have no financial or other potential conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

C.B. received research funds from Nutricia North America, Inc., Bethesda, MD, to study intestinal phosphate bioaccessibility and bioavailability in mice. He also serves on the Advisory Board for Bayer AG, Berlin, Germany.

Figures

Figure 1.
Figure 1.. Post-Translational Modification of FGF23.
FGF23 is a 251-amino acid 32 kDa protein. Phosphorylation by FAM20C at amino acid S180 is cleaved by FURIN into biologically-inactive FGF23 fragments. Unprocessed transcripts can also be O-glycosylated by GALNT3 into biologically-active FGF23. Cleavage by FURIN is suppressed by O-glycosylation of FGF23 and may be regulated by the elusive endocrine Pi sensor. The C-terminal fragment may serve as the endogenous inhibitor of KL-FGFR complex formation. FGF23 = Fibroblast growth factor 23 FAM20C = Extracellular kinase family member 20C FURIN = Subtilisin-like proprotein convertase GALNT3 = N-acetylgalactosaminyltransferase 3 KL-FGFR = Klotho – Fibroblast growth factor receptor complex
Figure 2.
Figure 2.. Canonical and Non-Canonical FGF23 Signaling.
FGF23 is a peptide hormone secreted by bone that affects multiple organ systems. A. In the proximal tubules, FGF23 caused internalization of sodium type 2 co-transporter NPT2a in a FGFR1c/KL-mediated manner by activation of ERK1/2 and SGK1 (red, canonical). FGF23 also decreased activation of vitamin D in a KL-independent fashion (blue, non-canonical). B. In the distal tubules, FGF23 causes KL-dependent stimulation of calcium and sodium reabsorption. C. In the parathyroid glands, FGF23 causes suppresses of PTH secretion, likely through KL-dependent and -independent pathways. D. In the heart, FGF23 causes LVH in a KL-independent manner in a FGFR4 mediated fashion mediated by PLCgamma/NFAT/calcineurin. E. In osteoblasts, FGF23 inhibits bone mineralization by decreased expression of the phosphatase TNAP in a KL-independent fashion. FGF23 = Fibroblast growth factor 23 FGFR = Fibroblast growth factor receptor NPT2a = Sodium-phosphate cotransporter 2a ERK1/2 = Extracellular signal-regulated kinases 1/2 SGK1 = Serum/glucocorticoid regulated kinase 1 WNK4 = Serine/threonine-protein kinase WNK4 NFAT = Nuclear factor of activated T-cells PLCgamma = Phosphoinositide phospholipase C gamma TNAP = tissue nonspecific alkaline phosphatases TRPV5 = transient receptor potential vanilloid 5 (calcium channel protein) NCC = Sodium-chloride cotransporter
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