The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis
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Masanobu Kawai
Abstract
The function of fibroblast growth factor (FGF) 23 has been suggested to be multifaceted beyond its canonical function as a regulator of mineral metabolism. FGF23 was originally shown to play a central role in phosphate (Pi) and vitamin D metabolism, and a number of diseases associated with dysregulated Pi metabolism have been attributed to abnormal FGF23 signaling activities. The discovery of Klotho as a co-receptor for FGF23 signaling has also accelerated understanding on the molecular mechanisms underlying Pi and vitamin D metabolism. In addition to these canonical functions, FGF23 has recently been implicated in a number of metabolic diseases including chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown. Molecular and functional insights into the FGF23 pathway will be discussed in the present review, with an emphasis on its role in human disorders related to dysregulated Pi metabolism as well as metabolic disorders.
Introduction
Fibroblast growth factor (FGF) 23 is a secretory molecule that is mainly produced by osteoblastic cells, and was originally shown to function as a central regulator of phosphate (Pi) and vitamin D metabolism. Since its identification in 2000 [1], extensive studies have been conducted in an attempt to reveal the role of FGF23 in the pathogenesis of human diseases associated with dysregulated mineral metabolism. The findings of these studies led to the development of new strategies to combat these disorders, and clinical trials for the treatment of X-linked hypophosphatemic rickets using FGF23-neutralizing antibodies are ongoing [2], [3]. Besides these canonical functions, FGF23 has recently been implicated in metabolic homeostasis. For example, FGF23 has been associated with a higher risk of cardiovascular disease (CVD) [4], [5], [6], [7], [8]. Furthermore, relationships have been reported between FGF23 concentrations and clinical parameters involved in glucose metabolism as well as inflammation [9], [10], [11], [12], [13], [14]; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown.
The discovery of α-Klotho (KL) as a co-receptor for FGF23 signaling has also accelerated understanding on the mechanisms responsible for the regulation of mineral metabolism [15]. Despite the critical roles of KL in FGF23 signaling, accumulating evidence has revealed a KL-independent pathway of FGF23, which may be involved in the non-canonical functions of FGF23 such as the development of cardiac hypertrophy. Thus, these novel findings have initiated a new era of research on the role of FGF23 signaling in human disorders. The canonical functions of FGF23/KL as a regulator of Pi and vitamin D metabolism will be discussed in the present review, with a focus on how its disturbance results in the development of human disorders associated with dysregulated mineral metabolism. The emerging roles of FGF23 beyond its involvement in mineral metabolism are also discussed.
Physiology of FGF23
The FGF23/KL axis
FGF23 was originally identified as a novel member of the FGF family [1] and is the gene responsible for hypophosphatemic rickets and osteomalacia [16], [17]. Although FGF23 was initially reported to be expressed in the brain, osteoblastic cells, particularly osteocytes, were subsequently identified as a physiological source of FGF23 [18], [19]. A number of other tissues including the thymus, small intestine, and heart have also been shown to express FGF23 [1], [16], but at lower levels and with an unknown physiological relevance. FGF23 contains a signal peptide in its N-terminus region and lacks the heparin-binding domain present in autocrine/paracrine FGFs [20]; therefore, FGF23 is able to escape from the extracellular matrix and function as an endocrine factor. Human FGF23 is a protein that comprises 251 amino acids (32 kDa), with rat and mouse FGF23 sharing 72% and 71% homologies to human FGF23, respectively. The N-terminal region of FGF23 is a FGF core homology domain and interacts with FGFRs, whereas the C-terminal domain is unique to FGF23 and binds KL [21], [22] (Figure 1).
Structure of FGF23.
Full-length FGF23 is proteolytically cleaved at the SPC motif to produce inactive forms of FGF23.
Significant advances in understanding on the roles of FGF23 have been accomplished by the discovery of KL functioning as a co-receptor for FGF23 [15]. KL was originally identified as the gene responsible for premature aging-like symptoms such as a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis, and emphysema in mice [23]. KL is a 135 kDa single-pass transmembrane protein that consists of an extracellular domain, transmembrane domain, and intracellular carboxyl domain [24]. The extracellular domain contains KL1 and KL2 internal repeats and exhibits weak β-galactosidase activity [25], [26]. In addition to its membrane localization, KL is known to be secreted into the circulation (soluble KL: sKL) and functions as a humoral factor that plays multiple roles in anti-oxidation, anti-apoptosis, and ion transport [26], [27], [28]. Approximately 130 kDa sKL is produced through the ectodomain shedding of membrane-bound KL by disintegrin and metalloproteinase (ADAM)-10, ADAM-17, and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) [29], [30] and has been detected in the urine, serum, and cerebrospinal fluid of humans [31]. Previous studies reported that 65–70 kDa sKL is also produced by alternative splicing; however, its presence in humans has not yet been confirmed [32], [33] (Figure 2).
Structure of Klotho (KL).
Membrane-bound KL (mKL) is composed of two internal repeats (KL1 and KL2), a transmembrane domain, and short intracellular carboxyl domain. The proteolytic cleavage of mKL at the transmembrane domain results in the production of 130 kDa soluble KL (sKL), while 65–70 kDa sKL is produced by alternative splicing.
Post-translational regulation of FGF23
One of the important features of FGF23 regulation is that it is proteolytically cleaved at the site of a subtilisin-like proprotein convertase (SPC) motif (176RXXR179). Cleavage at this site by proteases such as furin results in the inactivation of FGF23 and production of N- and C-terminal fragments [22]. C-terminal fragments have been shown to interact with KL and, as a consequence, function as antagonists of the FGF23 signaling pathway; therefore, the cleavage of this site may add another level to the mechanism by which the proteolytic cleavage of FGF23 impairs the FGF23 signaling pathway [34].
The cleavage of FGF23 at the SPC motif is known to be regulated by post-translational modifications. The glycosylation of Thr178 in the SPC motif by GALNT3 (polypeptide N-acetylgalactosaminyltransferase 3) is crucial for the production and secretion of full-length biologically active FGF23 [35], [36]. The phosphorylation of FGF23 adds another level to its regulatory network such that phosphorylation at Ser180 within the SPC motif by FAM20C has recently been reported to inhibit O-glycosylation by GALNT3, resulting in accelerated cleavage at this site [37], [38] (Figure 1).
Regulation of FGF23 expression
The regulatory network of FGF23 expression in bone cells has been widely examined and several signaling cascades have been shown to regulate its expression. As activation of the FGF23 signaling pathway decreases circulating Pi and 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels, it is important to determine whether any feedback loops are operative between FGF23 and Pi/1,25-(OH)2D. Pi and 1,25-(OH)2D have both been positively associated with FGF23 levels, indicating that FGF23 and Pi/1,25-(OH)2D mutually regulate each other and form a fine-tuned network in mineral metabolism. 1,25-(OH)2D is known to up-regulate the expression of FGF23 by activating the vitamin D receptor (VDR) [39], [40], [41]. Although VDR response elements have been reported in the mouse Fgf23 gene [41], the mode of in vivo regulation of human FGF23 by 1,25-(OH)2D has not yet been elucidated in detail.
In contrast to the regulation of FGF23 expression by 1,25-(OH)2D, it currently remains unclear whether Pi directly regulates the expression of FGF23. As accumulating evidence has indicated that extracellular Pi functions as a signaling molecule and transduces its signals in target cells, it is possible that Pi directly regulates the expression of FGF23 in bone cells. In support of this, in vivo animal models have revealed a relationship between dietary Pi loads and circulating FGF23 levels [42], [43], indicating that extracellular Pi induces the expression of FGF23; however, experimental evidence for the direct regulation of FGF23 by Pi is limited. Similar to the findings observed in mice, the amount of dietary Pi has been associated with serum FGF23 levels in humans [44], [45], although there is also evidence showing the lack of a relationship between these two parameters [46]. In order to determine the relationship between FGF23 and Pi, Scanni et al. analyzed the response of FGF23 to an acute Pi load in healthy humans, and found that an acute Pi load by an intravenous infusion or a duodenal Pi load increased FGF23 levels [47]. These increases were preceded by elevations in PTH, suggesting that the induction of FGF23 by an acute Pi load is partly mediated through an increase in PTH levels because PTH is known augment FGF23 levels. 1,25-(OH)2D concentrations were shown to be decreased after FGF23 levels increased [47].
PTH has also been identified as a positive regulator of skeletal FGF23 expression, as evidenced by clinical conditions in which PTH signaling is activated such as Jansen metaphyseal chondrodysplasia caused by a mutation in the PTH1R gene [48], [49]. In experimental animal models, intermittent injections of hPTH failed to induce FGF23 expression in mice lacking the PTH type 1 receptor in the limb mesenchyme, whereas it was induced in WT mice [50]. Chronic kidney disease (CKD) is an additional example of elevations in FGF23 levels being associated with increased PTH levels. The stimulatory role of PTH in FGF23 expression was experimentally proven in a rat CKD model in which parathyroidectomy reversed the elevated FGF23 levels in these rats [49]; however, evidence also exists that does not support this scenario [51]. In addition, clinical evidence for the relationship between PTH and FGF23 is limited. For example, FGF23 levels in patients with primary hyperparathyroidism were found to be similar to those in healthy controls [52]; therefore, the effects of PTH on FGF23 expression may be context-specific and further studies are clearly required to determine the role of PTH in the regulation of FGF23 expression.
We recently demonstrated that the expression of FGF23 was regulated by the sympathetic nervous system (SNS) [53]. As skeletal Fgf23 expression increases during the dark phase, in which food intake is stimulated in mice, we hypothesized that food intake may regulate FGF23 expression in the skeleton. SNS is activated by food intake; therefore, we determined whether the activation of SNS enhanced FGF23 expression. As expected, Fgf23 expression was induced by a β-adrenergic agonist in the skeleton and this effect was mediated through a cAMP-response element located in the promoter region in the Fgf23 gene. In order to better understand the relationships between food intake, the SNS, and FGF23 expression, mice were exclusively fed during the light phase. Under these conditions, a peak in SNS activity was shifted from the dark to light phase and this was associated with a peak expression of Fgf23 during the light phase [53]. Furthermore, when a β-blocker was concomitantly used, a peak in the expression of Fgf23 was not observed. These findings suggest that the timing of food intake determines the rhythmic expression profile of skeletal Fgf23, and also that food intake-driven sympathetic activation is critical in this regulation. This system may function as part of the systemic regulatory network maintaining Pi levels such that the enhanced influx of Pi from the diet is balanced by the food intake-associated induction of FGF23 to stimulate the excretion of Pi in the urine.
In addition to the factors described above, numerous factors have been implicated in the regulation of FGF23 expression. For example, activation of the FGF signaling pathway has been suggested to activate FGF23 expression, as demonstrated in patients with osteoglophonic dysplasia caused by the activation of mutations in the FGFR1 gene, which increases FGF23 levels [54]. In vivo and in vitro analyses also experimentally support this [55], [56], [57], [58]. The activation of FGFR by low molecular weight (LMW) FGF2 was shown to increase the expression of FGF23 through activation of NFAT pathway [57], [58]. In addition to the activation of membrane FGFR by FGF2, the intranuclear activation of FGFR1 by high molecular weight (HMW) FGF2 was also found to increase the expression of FGF23, possibly in a manner involving the activation of CREB pathway [57]. Hypoxia has been shown to induce FGF23 expression, and hypoxia inducible factor-1 (HIF1) is suggested to be involved in this regulation [59]. HIF1 has also been reported to be involved in the induction of FGF23 by inflammation and iron deficiency [60]. FGF23 levels were also reported to be positively associated with the biomarkers of inflammation, insulin resistance, myocardial infarction, and metabolic acidosis [9], [10], [11], [12], [13], [14]; however, the molecular mechanisms underlying the induction of FGF23 under these conditions have not yet been elucidated in detail (Figure 3).
Regulation of FGF23 expression.
The numerous factors regulating FGF23 transcription have been identified, but the underlying molecular cascades remain largely unknown. VD, 1,25(OH)2 vitamin D; PTH, parathyroid hormone; PTHR, PTH receptor; SNS, sympathetic nervous system; β-AR, beta adrenergic receptor; LMW-FGF2, low molecular weight; FGFR, FGF receptor; sKL, soluble Klotho; VDR, vitamin D receptor; CREB, cAMP response element binding protein; NFAT, nuclear factor of activated T-cells, HMW-FGF2, high molecular weight FGF2; HIF1, hypoxia inducible factor-1.
The FGF23 signaling pathway
Since KL is required for FGF23 to exert its effects, KL-expressing tissues are considered to be the target tissues of the FGF23 signaling pathway. KL is expressed in various tissues including the parathyroid gland, placenta, pituitary, and choroid plexus of the brain [23], with the distal tubular epithelial cells of the kidney being the strongest expressers of KL [23]. In these tissues, FGF23 binds to FGF receptors and activates downstream pathways such as the extracellular signal-regulated kinases (ERK)/early growth response-1 (EGR-1) signal pathway. FGF23 has been shown to bind to FGFR1, 3c, and 4 in vitro [61], whereas the in vivo relevance of this complex may be restricted to FGFR1 [62], [63].
In contrast to the widely accepted tenet that membrane-bound KL is required for the FGF23 signaling pathway, accumulating evidence has revealed that FGF23 exerts its effects in cooperation with sKL, which also makes a complex with FGF23 and FGFR and activates downstream signaling cascades [61], [64], [65]. The in vivo implications of the FGF23/sKL complex were previously analyzed using a mouse model in which sKL was overexpressed [65]. The FGF23/sKL complex has been proposed to activate FGFRs and induce FGF23 expression in osteoblastic cells. It may also play a role in the regulation of chondrocyte biology such that FGF23/sKL binds to FGFR3 and suppresses chondrocyte proliferation [64]. These findings suggest that FGF23 transduces its signals in cells in which membrane-bound KL is not expressed; however, whether this scenario is operative under physiological conditions remains to be determined since these findings were based on the use of supraphysiological levels of sKL.
In addition to the KL-dependent effects of FGF23, accumulating evidence indicates the presence of a KL-independent function of FGF23. For example, FGF23 has been shown to induce left ventricular hypertrophy by activating the calcineurin-NFAT signaling pathway independent of KL, and the FGFR4/PLCγ pathway was subsequently shown to be activated by FGF23 in cardiac myocytes when KL was absent [66], [67]. Additionally, FGF23 has been reported to suppress the secretion of PTH in a KL-independent manner; however, KL-dependent signaling pathway also plays an important role in this regulation, [68], [69]. Although these findings emphasize the presence of the KL-independent signaling pathway of FGF23, the molecular mechanisms by which FGF23 binds and activates FGFR in the absence of KL remain unknown (Figure 4).
FGF23 signaling cascades.
FGF23 activates its downstream signaling molecules including FRS2α and ERK in co-operation with Klotho, and this is involved in the regulation of mineral metabolism and PTH production. In the absence of Klotho, FGF23 may activate the calcineurin/NFAT signaling pathway, regulate PTH production, and induce cardiac hypertrophy; however, the mode of binding between FGFR and FGF23 in this scenario has not yet been determined. Pi, Inorganic phosphate; VD, vitamin D.
Functions of the FGF23/KL signaling pathway
Regulation of Pi metabolism
Genetically engineered mouse models have revealed the central role of the FGF23/KL axis in the regulation of Pi homeostasis; Fgf23-deficient mice and Klotho-deficient mice displayed almost identical phenotypes in the context of Pi metabolism such that both animal models exhibit increases in Pi levels with reduced urinary Pi excretion [70]. In a similar manner, FGF23 transgenic mice display hypophosphatemia [71], [72]. The strict requirement of KL in this regulation is also evident in a mouse model in which the KL/FGF23 axis is disrupted. An injection of recombinant FGF23 (rFGF23) into WT or Fgf23-deficient mice caused a decrease in Pi levels, whereas this effect of rFGF23 was not observed in Klotho-deficient mice. The phosphaturic effects of FGF23 are mainly mediated through its actions in KL-expressing cells in the distal tubular epithelial cells of the kidney because the partial deletion of Klotho in these cells partly recapitulates the phenotypes of Fgf23-deficient and Klotho-deficient mice [73]. The administration of rFGF23 to WT mice was consistently shown to activate its downstream molecules in distal tubular epithelial cells and result in the development of hypophosphatemia [17], [74].
The phosphaturic effects of the FGF23/KL axis are predominantly dependent on its regulation of the renal expression and localization of type II Na+-dependent Pi co-transporters, particularly Npt2a and Npt2c. Activation of the FGF23 signaling pathway has been shown to suppress the expression and activities of Npt2a and Npt2c and reduce the renal reabsorption of Pi [74], [75]. In addition, as described later, activation of the FGF23 pathway is known to reduce 1,25-(OH)2D levels in the circulation, which, in turn, decreases the intestinal absorption of Pi and may contribute to reductions in circulating Pi levels in response to the activation of FGF23. It is important to note that renal Npt2a and 2c are predominantly expressed in the proximal tubular epithelial cells, which is distinct from the predominant expression of KL in the distal tubular epithelial cells [76], [77]; therefore, the mechanisms by which the activation of FGF23 signaling in distal tubular epithelial cells affects Npt2a and Npt2c expression in the proximal tubules remains unclear. Nevertheless, the existence of secretory molecules that mediate this connection has been suggested. The weak expression of KL in the proximal tubules may also explain the regulation of Npt2a and 2c by FGF23 [78]; however, further analyses are clearly needed in order to elucidate the underlying mechanisms.
Regulation of vitamin D metabolism
In addition to its critical roles in the regulation of Pi metabolism, the FGF23/KL axis also regulates the synthesis of 1,25-(OH)2D. Activation of the FGF23/KL signaling pathway decreases circulating levels of 1,25-(OH)2D by suppressing Cyp27b1 expression, which encodes 1-α-hydroxylase, an enzyme that converts 25-dihydroxyvitamin D to 1,25-(OH)2D and increases the expression of Cyp24a1, encoding for 24-hydroxylase, resulting in the inactivation of 1,25-(OH)2D [74]. The expression of KL in the parathyroid gland may also affect the synthesis of 1,25-(OH)2D. Animal studies have suggested that activation of the FGF23/KL pathway in the parathyroid gland suppresses the expression and secretion of PTH [69]; therefore, the effects of FGF23 on the suppression of 1,25-(OH)2D production may, at least partly, be mediated through the inhibited production of PTH because PTH is known to enhance the expression of Cyp27b1 in the kidney. Although increasing evidence from animal studies has demonstrated the suppressive effects of FGF23 on PTH production, it is still unclear whether this pathway is operative in humans because FGF23 fails to suppress PTH levels in some human disorders. For example, elevations in FGF23 levels in CKD patients are often associated with secondary hyperparathyroidism. Thus, the precise roles of FGF23 in the regulation of PTH expression under physiological and/or pathogenic conditions have yet to be determined.
Human diseases related to a dysregulated FGF23/KL axis
Enhanced FGF23/KL axis
X-linked hypophosphatemic rickets (XLH)
XLH is a disorder caused by a mutation in the PHEX gene (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome). A loss-of-function mutation in this gene has been shown to enhance the production of FGF23 and cause hypophosphatemia [79]; however, the molecular mechanism by which the lack of PHEX increases FGF23 production currently remains unclear. A clinical trial on the use of neutralizing antibodies raised against FGF23 (KRN23) is currently underway, and has been reported to successfully reverse hypophosphatemia and increase 1,25-(OH)2D levels [2], [3]. However, the effectiveness of KRN23 in improving skeletal abnormalities has not yet been reported; therefore, future studies are needed in order to assess the effectiveness of this new therapy in XLH patients.
Autosomal-dominant hypophosphatemic rickets (ADHR)
A gain-of-function mutation in the FGF23 gene is responsible for ADHR, which is characterized by rickets, osteomalacia, a short stature, bone pain, and dental abscesses [16]. Mechanistically, the substitution of Arg to Gln at position 176 (R176Q) in the SPC motif has been shown to inhibit the proteolytic cleavage of FGF23, which results in activation of the FGF23/KL signaling pathway. The iron status has recently been linked to the development of ADHR phenotypes [59]. Using a mouse model in which the R176Q mutation was knocked-in, an iron deficiency was found to up-regulate the expression of Fgf23 in ADHR mice, but not in WT mice [59]. A similar scenario may occur in humans based on the clinical observation that the successful withdrawal of rickets medications was achieved in ADHR patients taking high doses of iron [80].
Autosomal-recessive hypophosphatemic rickets (ARHR) 1 and 2
Mutations in the DMP1 (dentin matrix protein 1) and ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) genes are responsible for ARHR 1 and 2, respectively. Mutations in these genes up-regulate the expression of FGF23 and result in hypophosphatemic rickets; however, the mechanisms responsible are currently unknown [81], [82], [83].
Tumor-induced osteomalacia (TIO)
TIO is a rare paraneoplastic syndrome in which elevated FGF23 levels produced by endocrine tumors are associated with hypophosphatemia and inappropriately normal or low levels of 1,25-(OH)2D [84]. Abnormal mineral metabolism results in the development of osteomalacia and rickets, and clinical symptoms ares successfully treated by surgical removal of the tumors responsible.
Mutations in the FAM20C gene
Mutations in the FAM20C gene, known to be responsible for Raine syndrome, have recently been implicated in the autosomal-recessive form of the disorder characterized by elevations in FGF23 levels, hypophosphatemia, dental anomalies, and ectopic calcifications [85], [86]. The FAM20C protein was initially reported to be a kinase that phosphorylates SIBLING proteins (small integrin-binding ligand N-linked glycoproteins) such as DMP-1 and OPN [87]. FGF23 was subsequently shown to be phosphorylated at Ser 180 by FAM20C, and the phosphorylation of FGF23 at this site has been suggested to inhibit the O-glycosylation of FGF23 by GALNT3, which enhances the proteolytic cleavage of FGF23 [37], [38]; therefore, hypophosphatemia in these patients may be caused by decreases in the cleavage of FGF23 through the loss of functional mutations in the FAM20C gene.
Others
Elevated FGF23 levels have been detected in McCune-Albright syndrome, caused by an activating mutation in the GNAS gene [19], osteoglophonic dysplasia, caused by a heterozygous mutation in the FGFR1 gene [54], and Jansen metaphyseal chondrodysplasia, caused by a mutation in the PTH1R gene [48]. Chromosomal translocations with a breakpoint adjacent to the KLOTHO gene were previously reported to enhance KL expression and cause hypophosphatemic rickets due to enhanced stimulation of the FGF23/KL signaling pathway [88].
Reduced FGF23/KL axis
Familial tumoral calcinosis
Mutations in the FGF23 gene [89], [90] and GALNT3 gene [35], [91], [92], [93] cause hyperphosphatemic familial tumoral calcinosis. The loss of a functional mutation in the FGF23 gene enhances the susceptibility of the mutated protein to proteolytic cleavage, thereby decreasing intact FGF23 concentrations. As described above, GALNT3 is known to O-glycosylate FGF23 at Thr178 and protect FGF23 from proteolytic cleavage; therefore, the loss of a functional mutation in the GALNT3 gene results in the accelerated cleavage of FGF23, which causes hyperphosphatemia.
Mutation in the KLOTHO gene
The loss of a functional mutation in the KLOTHO gene was discovered in a patient with familial tumoral calcinosis [94]. This patient possesses a H193R mutation in the KLOTHO gene, and this mutated protein decreases FGF23 signaling and causes hyperphosphatemia.
Emerging roles of FGF23 in metabolic homeostasis
Adipose tissue biology
A growing body of evidence from clinical studies has highlighted the relationship between FGF23 and the metabolic status such as insulin resistance, dyslipidemia, and obesity [95]. Hanks et al. recently investigated the relationship between FGF23 and markers for insulin resistance, and reported a positive association between FGF23 and HOMA-IR [12]. Fernandez-Real et al. also described similar findings [96]. In the latter study, weight loss was associated with decreases in HOMA-IR and FGF23. Mirza et al. examined the relationship between FGF23 and obesity-related markers in elderly subjects, and found that FGF23 levels positively associated with fat mass and triglyceride levels, but not with HOMA-IR [97]. These findings suggest that the FGF23 signaling pathway plays important roles in the pathogenesis of obesity and obesity-associated complications; however, other studies reported a negative association between theses parameters [98], [99]. Therefore, further clinical investigations are clearly required in order to determine the role of FGF23 in the regulation of obesity in humans.
Animal models have also suggested the involvement of the FGF23/KL axis in the regulation of adipose tissue biology. Klotho-deficient mice exhibit a markedly smaller white adipose tissue (WAT) mass, which is associated with enhanced insulin sensitivity and low glucose levels. Intra-abdominal WAT is almost undetectable, whereas inguinal WAT (iWAT) is present, albeit at an extremely reduced amount [100]. Although a histological analysis of iWAT revealed the significantly reduced accumulation of lipid droplets, this was unlikely a consequence of lipodystrophy because of the absence of macrophage infiltration and fibrotic changes [100]. In vivo and in vitro analyses have been performed in order to investigate the mechanisms by which the lack of KL affects fat depots. KL has been proposed to have direct effects on adipocyte metabolism, and its overexpression in the preadipocytic cell line, 3T3-L1, has been shown to stimulate adipogenesis [101]. The expression levels of Kl were more than 1000-fold lower in white adipose tissue than in the kidney in C57BL/6 mice [100]; therefore, it is still unclear whether the expression of physiological levels of KL in adipose tissue has any impact on adipocyte biology. In addition to its direct effects on adipocytes, the lack of KL may affect adipocyte biology through alterations in mineral homeostasis. Consistent with this notion, decreases in WAT were found to be partially rescued by the correction of hyperphosphatemia in Klotho-deficient mice [102], suggesting that hyperphosphatemia is, at least partly, a cause of the decreased fat mass in these mice; however, the mechanisms by which increases in phosphate levels decrease the fat mass remain to be determined.
Regarding the role of FGF23 in BAT function, Klotho-deficient mice are hypothermic and not able to tolerate the cold [103]. The expression of Ucp1 is down-regulated in the BAT of Klotho-deficient mice [100], [103]. As the lack of Kl does not affect brown adipogenesis or the induction of Ucp1 by forskolin in mature brown adipocytes, BAT dysfunction in Klotho-deficient mice may not be a consequence of the lack of KL in BAT [100]. We recently demonstrated that hyperphosphatemia was responsible for impaired BAT function in Klotho-deficient mice [100]. Mechanistically, increases in extracellular Pi activate the AKT/mTORC pathway by suppressing PTEN, and mTORC1 activation causes a decrease in the mitochondrial membrane potential and enhances oxidative damage [100]. The blockade of mTORC1 by rapamycin was found to consistently improve BAT function in Klotho-deficient mice [100]. Taken together, these findings implicate FGF23 in the regulation of adipocyte biology; however, evidence to support this notion is still limited.
CKD
In patients with CKD, FGF23 levels increase in the early stage of CKD and precede elevations in PTH and Pi levels [46], [104], [105], [106], [107]. As clinical studies have revealed a relationship between increases in FGF23 levels and a higher risk of CVD and mortality [5], [7], [8], [108], [109], [110], extensive studies have been conducted in order to test the hypothesis that increases in FGF23 levels may be pathogenically involved in the development of CKD-related complications, and the efficacy of the blockade of FGF23 signaling by FGF23-neutralizing antibodies has been examined in CKD animal models. However, the efficacy of this blockade has not been consistently reported. A previous study showed that the blockade of FGF23 signaling increased mortality, even though it ameliorated hyperparathyroidism [111]. It is also possible that FGF23 levels increase in order to reduce the retention of Pi as part of a compensatory mechanism; however, due to concomitant decreases in KL expression in the kidney [112], [113], this compensatory mechanism may not be effectively operative in CKD. Although the mechanisms responsible for increases in FGF23 levels in CKD are not fully understood, higher FGF23 mRNA levels in osteocytes and extra-skeletal tissues such as the heart, and the prolonged half-life of FGF23 in the circulation may contribute to the elevations in FGF23 levels observed in CKD [114], [115].
CVD
Increases in FGF23 levels have been associated with a higher risk of CVD regardless of the presence of renal dysfunction [4], [5], [6], [7], [8]. Despite increasing clinical evidence, it still remains unclear whether increases in FGF23 levels are pathogenic to these conditions. In order to elucidate the role of FGF23 in the development of CVD, an intravenous or intramyocardial injection of rFGF23 was administered to mice, and FGF23 was found to induce ventricular hypertrophy [66]. Cardiac hypertrophy was induced, even in mice lacking Klotho, suggesting the KL-independent effects of FGF23. The effects of FGF23 in the development of cardiac hypertrophy were subsequently shown to involve FGFR4 and its downstream activation of the PLCγ/calcineurin/NFAT pathway [67]. Additionally, FGF23 has been detected in cardiac myocytes under pathogenic conditions [116], further supporting the possibility of FGF23 as a cause of CVD. As Pi is also known to be associated with the development of CVD, the role of FGF23 in the development of CVD is, at least partly, mediated through alterations in Pi homeostasis. However, some clinical studies have identified FGF23 as a risk factor for CVD independent of Pi levels [116]. Regarding the role of KL in CVD, serum levels of sKL have been negatively associated with the risk of CVD in humans [117]. Animal models also demonstrated that the lack of KL in mice caused left ventricular hypertrophy. Since the lack of Klotho in mice causes an increase in FGF23 levels, the KL-independent effects of FGF23 may play a role in the development of cardiac hypertrophy even though sKL itself has been shown to have protective effects against cardiac hypertrophy by down-regulating TRPC6 channels [118]. Although accumulating evidence indicates the critical roles of FGF23 and KL in cardiovascular biology, the underlying mechanisms are complex and additional clinical and basic studies are clearly required in order to understand the precise roles of FGF23 and KL in this regulation.
Concluding remarks
A growing of body of evidence clearly demonstrates that the FGF23/KL signaling network plays central roles in the regulation of mineral metabolism, and multiple disorders associated with dysregulated Pi metabolism have been attributed to disturbances in this pathway. Our knowledge on FGF23/KL in the pathogenesis of these disorders has recently been expanded to the commencement of clinical trials for the treatment of XLH. Beyond concrete evidence for the role of FGF23 in Pi metabolism, clinical and basic studies have opened a new field in which FGF23 signaling is involved in the pathogenesis of metabolic diseases including CKD-related complications, obesity-related disorders, and CVD. These novel findings have clearly provided us with opportunities to target FGF23 in order to combat these disorders; however, clinical and basic evidence to support this notion is still limited. Notwithstanding, future studies will undoubtedly prove the roles of FGF23 in these disorders and provide us with opportunities to target FGF23 for the treatment of FGF23-related metabolic disorders.
Acknowledgments
This work was supported by a grant from JSPS KAKENHI (Grant Number 26461558).
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©2016 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Editorial Preface
- Preface to special issue on ‘Endocrine functions of bone: new (patho)-physiological and clinical insights’
- Topic A: Endocrine Functions of Bone and Bone Marrow Adipose Tissue: Hormonal, Molecular, Nutritional Mechanisms
- Review Articles
- The “soft” side of the bone: unveiling its endocrine functions
- Bone marrow adipose tissue as an endocrine organ: close to the bone?
- The dietary protein, IGF-I, skeletal health axis
- The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis
Artikel in diesem Heft
- Frontmatter
- Editorial Preface
- Preface to special issue on ‘Endocrine functions of bone: new (patho)-physiological and clinical insights’
- Topic A: Endocrine Functions of Bone and Bone Marrow Adipose Tissue: Hormonal, Molecular, Nutritional Mechanisms
- Review Articles
- The “soft” side of the bone: unveiling its endocrine functions
- Bone marrow adipose tissue as an endocrine organ: close to the bone?
- The dietary protein, IGF-I, skeletal health axis
- The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis
