The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis

Abstract

Normal mineral ion homeostasis is tightly controlled by numerous endocrine factors that coordinately exert effects on intestine, kidney, and bone to maintain physiological balance. The importance of the fibroblast growth factor (FGF)-23-klotho axis in regulating mineral ion homeostasis has been proposed from recent research observations. Experimental studies suggest that 1) FGF23 is an important in vivo regulator of phosphate homeostasis, 2) FGF23 acts as a counter regulatory hormone to modulate the renal 1alpha-hydroxylase and sodium-phosphate cotransporter activities, 3) there is a trend of interrelationship between FGF23 and parathyroid hormone activities, 4) most of the FGF23 functions are conducted through the activation of FGF receptors, and 5) such receptor activation needs klotho, as a cofactor to generate downstream signaling events. These observations clearly suggest the emerging roles of the FGF23-klotho axis in maintaining mineral ion homeostasis. In this brief article, we will summarize how the FGF23-klotho axis might coordinately regulate normal mineral ion homeostasis, and how their abnormal regulation could severely disrupt such homeostasis to induce disease pathology.

Figure 1

Schematic diagram showing the structure of full-length FGF23 protein (A) with its putative signal peptide (aa 1–24), the amino terminal of FGF23 (aa 25–179) has the homologous region to other known FGFs; the carboxy terminal of FGF23 (aa 180–251) might have possible klotho-interacting site. Moreover, aa 176–179 represents the subtilisin-like cleavage site, where full-length FGF23 protein is cleaved into the smaller 18 kDa amino-terminal and the 12 kDa carboxy-terminal fragments (B). Mutations in ¹⁷⁶R and ¹⁷⁹R have been reported in patients with ADHR, whereas mutations in ⁷¹S, ⁹⁶M, and ¹²⁹S have been associated with patients affected by FTC. FGF23 has been shown to be O-glycosylated by the enzyme GALNT3 and the major glycosylation site is believed to be ¹⁷⁸T, as shown in the diagram. Klotho protein (C) is composed of 1014 amino acids, and possesses a putative signal sequence (SS) at its N-terminus and a putative transmembrane domain (TM) with a short cytoplasmic domain (CD) at the C-terminus. The extracellular domain of the klotho protein consists of two internal repeats (KL1 and KL2) that share sequence homology to the β-glucosidase.

Figure 2

Altered mineralization in bone and kidney of Fgf23 knockout (Fgf23^−/−) mice. Note abnormal nodular lesions (arrow) in the ribs of Fgf23^−/− mice, compared with control (A). Histomorphometric analysis on methyl methacrylate sections, stained with toluidine blue and von Kossa’s stains, shows increased mineral deposition (black) in the mutant ribs (asterisk; B). It is worth to mention that in Fgf23^−/− mice, skeletal mineralization has heterogeneous distribution, where increased mineral deposition is also accompanied with unmineralized osteoid (light blue) formation (B). Extensive soft tissue mineralization is a characteristic feature in Fgf23^−/− mice, as shown here in the kidney (C).

Figure 3

Schematic outline of FGF23–FGFR interactions. Signaling of FGF23–FGFR involves klotho as a cofactor to induce such downstream signaling molecules as Erk1/2, which could influence the activation of Egr-1. FGF23 also induces Nab-2 (Fukuda et al. 2007), specific corepressor of Egr-1 that could suppress the transcriptional activity of Egr-1, and thereby establish a negative feedback loop to regulate physiological activities of FGF23.