Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism

Abstract

The metabolically active and perpetually remodeling calcium phosphate-based endoskeleton in terrestrial vertebrates sets the demands on whole-organism calcium and phosphate homeostasis that involves multiple organs in terms of mineral flux and endocrine cross talk. The fibroblast growth factor (FGF)-Klotho endocrine networks epitomize the complexity of systems biology, and specifically, the FGF23-αKlotho axis highlights the concept of the skeleton holding the master switch of homeostasis rather than a passive target organ as hitherto conceived. Other than serving as a coreceptor for FGF23, αKlotho circulates as an endocrine substance with a multitude of effects. This review covers recent data on the physiological regulation and function of the complex FGF23-αKlotho network. Chronic kidney disease is a common pathophysiological state in which FGF23-αKlotho, a multiorgan endocrine network, is deranged in a self-amplifying vortex resulting in organ dysfunction of the utmost severity that contributes to its morbidity and mortality.

Figure 1

Phylogenetic tree of human fibroblast growth factor (FGF). Branch lengths represent the evolutionary distance between each gene. Gray represents the paracrine/autocrine subfamilies. Blue denotes the FGF11 subfamily of intracellular mediators that work independently of FGF receptors. Red represents the endocrine subfamily where the peptide hormone circulates. Adapted from Itoh & Ornitz (182).

Figure 2

The endocrine fibroblast growth factor (FGF)-Klotho axes. The FGF15/19-βKlotho axis is essential for postprandial negative feedback regulation of bile acid synthesis and release. FGF15/19 increase hepatic glycogen and protein synthesis (183), induce a lean phenotype (45, 46), and exert postprandial negative feedback of bile acid synthesis, functioning as a satiety hormone (47). In contrast, FGF21 is a fasting hormone (48). FGF21 is secreted from liver upon starvation and acts on white adipose tissue where βKlotho and FGFR1c are coexpressed (39). FGF21 expression is stimulated by ketogenic diet and peroxisome proliferator-activated receptor alpha (PPARα) agonists (49, 50). FGF21 induces resistance to growth hormone and torpor and promotes fatty acid oxidation, gluconeogenesis, and ketogenesis in the liver by increasing hepatic PGC1α expression (49, 52, 53). In white adipose tissue, FGF21 promotes lipolysis, mitochondrial respiration, and thermogenesis (–53). FGF23 biology primarily concerns mineral metabolism by acting on the kidney and parathyroid glands. Abbreviations: FGFR, fibroblast growth factor receptor; FXR, farnesoid X receptor; P_i, phosphate; PTH, parathyroid hormone; VDR, vitamin D receptor.

Figure 3

Fibroblast growth factor (FGF) 23, Klotho family members, and the FGF23-FGF receptor (FGFR)-Klotho complex. (a) Structure of FGF23 showing the three main domains of this small polypeptide. The N terminus shares homology with other FGFs, whereas the C terminus is unique and binds to its cognate receptor (green). FGF23 circulates in the blood as both intact (full-length) and physiologically cleaved fragments. The C terminus binds but does not transactivate the FGFR-Klotho complex and can potentially function as a competitive antagonist. (b) Klotho family showing the three members identified to date in the mammalian genome, all of which are single-transmembrane proteins of varying lengths. Homologous motifs termed Kl domains are conserved. Soluble forms of αKlotho can be generated by alternative splicing of its transcript or by proteolytic cleavage of the transmembrane form by β-secretases into various body fluids. The major organs of expression of αKlotho, βKlotho, and γKlotho are shown in bold. (c) 2FGF23: 2FGFR:2αKlotho complex. The FGFR (blue) has three immunoglobulin-like domains (D1, D2, D3) that are stabilized by internal disulfide bridges. The heparin-binding region in the generic FGFR is shown (purple). For the endocrine FGF ligands, the coreceptor function of heparan sulfate is replaced by Klotho. αKlotho forms complexes with FGFR1c, FGFR3c, and FGFR4 and serves as the high-affinity receptor for FGF23. The ligand-binding region (green) interacts with the C terminus of FGF23. Klotho has a negligible intracellular region, whereas the FGFR has two kinase domains that sustain signal transduction. Abbreviations: GI, gastrointestinal; RHTR, arginine-histidine-threonine-arginine.

Figure 4

Endocrine regulation of phosphate (P_i) and calcium metabolism. (a) Multiple negative feedback loops between the principal regulators of mineral metabolism: parathyroid hormone (PTH), fibroblast growth factor (FGF) 23, Klotho, and vitamin D. The kidney is a major contributor to circulating blood Klotho. Klotho is postulated to suppress FGF23 production from bone. Klotho functions as a coreceptor of FGFR allowing FGF23 to suppress PTH. PTH increases plasma levels of FGF23 and vitamin D. Increased vitamin further stimulates FGF23 and directly and indirectly suppresses PTH. Increased vitamin D also stimulates Klotho production in the kidney. Through several negative or positive feedback loops, Klotho functions as both a P_i-regulatory hormone and a calcium-regulatory hormone. (b) A change in one parameter triggers a cascade of events starting with hypocalcemia. Ionized calcium usually inhibits PTH secretion (1). When plasma-ionized calcium levels are low, PTH is stimulated, which promotes synthesis of active vitamin D (2), which in turn increases intestinal absorption of calcium and P_i (3). PTH also leads to renal calcium retention (4) and increased bone turnover (5). These act in concert (3–5) to restore plasma ionized calcium. When blood P_i levels and/or P_i intake is increased, FGF23 is increased (6). FGF23 suppresses vitamin D directly (7) and indirectly by suppressing PTH (, 8) in a Klotho-dependent manner. Together with its phosphaturic activity (9), FGF23 induces negative P_i balance. FGF23 is also increased by vitamin D (10) and PTH (11), thereby closing negative feedback loops between FGF23, PTH, and vitamin D.

Figure 5

Proposed time profile of changes in blood phosphate (P_i), calcium, Klotho, and hormones relevant to mineral metabolism in chronic kidney disease (CKD). The decrease in Klotho protein in the kidney and blood is an early event in CKD and is sustainably and progressively reduced along with the decline of renal function. Low Klotho partially induces fibroblast growth factor (FGF) 23 resistance, causing an initial compensatory increase in blood FGF23 to maintain P_i homeostasis. Increase in FGF23 decreases vitamin D levels and is followed by elevation of parathyroid hormone (PTH). Hyperphosphatemia is a relatively late event in advanced CKD; normal range is shown in gray. The scale is not meant to be truly proportionate; e.g., the elevation of FGF23 is massive in CKD compared with the elevation of parathyroid hormone. The x axis represents decline in renal function from stage 1 to 5 of CKD based on estimated glomerular filtration rate (eGFR).

Figure 6

Pathophysiological role of Klotho deficiency in disturbed mineral metabolism and complications of chronic kidney disease-mineral and bone disease (CKD-MBD). (a) A sequence of events that constitutes a positive feedback, self-exacerbating downhill spiral. In CKD and end-stage kidney disease, the normal interactive network is deranged. Each of the hormonal disturbances is amplified by phosphate (P_i) loading (blue asterisks). Both renal and plasma Klotho are decreased. The downregulation of Klotho increases fibroblast growth factor (FGF) 23 production, which in turn suppresses vitamin D production in the kidney. Low blood Klotho will blunt the suppressive effect of FGF23 on parathyroid hormone (PTH) production. In addition, decreased FGFR1 and Klotho in the uremic parathyroid gland render the gland resistant to the suppressive effect of FGF23 and triggers and/or promote secondary hyperparathyroidism. High blood PTH further stimulates FGF23 production. Hyperphosphatemia amplifies the high FGF23 and PTH and low Klotho. Low vitamin D downregulates renal Klotho expression directly and indirectly via intrarenal angiotensin II (Ang II), which further reduces renal Klotho production. (b) High plasma PTH, P_i, and FGF23 and low plasma vitamin D and Klotho contribute in concert to the development of complications such as metabolic bone disease, secondary hyperparathyroidism, cardiomyopathy, and vascular calcification. Dashed lines depict proposed but unproven roles of the metabolic disturbances.