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NDT Advance Access originally published online on March 29, 2007
Nephrology Dialysis Transplantation 2007 22(6):1524-1526; doi:10.1093/ndt/gfm122
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Klotho spins the thread of life—what does Klotho do to the receptors of fibroblast growth factor-23 (FGF23)?*

Tilman B. Drüeke1 and Dominique Prié2

1Inserm Unité 845 and Service de Néphrologie and 2Service de Physiologie-Explorations Fonctionnelles and Inserm Unité 845, Hôpital Necker, Assistance Publique-Hôpitaux de Paris and Faculté de Médecine René Descartes Paris 5, Paris, France

Correspondence and offprint requests to: T. B. Drüeke, MD, FRCP, Inserm Unité 845, Hôpital Necker, Tour Lavoisier, 161 rue de Sèvres, F-75743 Paris Cedex 15 France. Email: drueke{at}necker.fr

Keywords: FGF23; FGF receptors; kidney; Klotho; phosphate; vitamin D

Klotho is one of the three goddesses of the Moirae, who in Greek mythology control the life and destiny of everyone. She is the goddess who helps life to unfold, in contrast to the (apoptotic) goddess Atropos, who cuts the thread of life.

Prolonging lifespan is probably the most important role of the ageing-suppressor gene Klotho, named after the Greek goddess. Klotho was identified 10 years ago, by the Japanese group of Kuro-o et al. [1]. They reported that a defect in Klotho gene expression in the mouse resulted in a syndrome that resembled human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encoded a membrane protein that shared sequence similarity with the beta-glucosidase enzymes. This led them to conclude that the protein might function as part of a signalling pathway involved in the regulation of ageing and related diseases. One year later, the same group isolated the human homologue of the Klotho gene and determined its structure [2].



   Why is Klotho of particular interest for nephrology?
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Regulation of FGF23 signalling...
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First of all, Klotho is involved in the renal control of calcium, phosphate and vitamin D metabolism. It suppresses phosphate re-absorption in renal proximal tubule, by directly binding to FGF receptors [3]. It regulates Ca2+ re-absorption in the distal convoluted tubule by stabilizing the TRPV5 Ca2+ channel in the plasma membrane [4]. It inhibits renal 1-alpha 25 hydroxylase activity and thereby decreases circulating calcitriol levels [5]. It therefore appears to synergize with the renal tubular effects of parathyroid hormone (PTH) on Ca2+ and phosphate transport, whereas it antagonizes the stimulatory effect of PTH on calcitriol synthesis by the kidney (Figure 1).


Figure 1
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  		Fig. 1. Effect of FGF23 + Klotho on renal tubular re-absorption of inorganic phosphate (iP) and synthesis of 1,25 dihydroxy vitamin D (calcitriol). FGF23 + Klotho act synergistically with parathyroid hormone (PTH) to reduce tubular iP re-absorption. However, FGF23 + Klotho inhibit tubular calcitriol synthesis, in contrast to PTH which stimulates it. In end-stage renal disease (ESRD), the physiological inhibition of tubular iP re-absorption by both PTH and FGF23 + Klotho becomes ineffective. The concomitant increase in PTH secretion leads to excessive iP release from bone into the extracellular space. The clinical consequence is hyperphosphataemia.

 
Second, Klotho-deficient mice and fibroblast-growth factor-23 (FGF23)-deficient mice have an identical phenotype including hyperphosphataemia, hypercalcaemia, elevated plasma calcitriol and vascular calcification, in addition to premature ageing [1,6,7]. In contrast, over-expression of the Klotho gene extends the lifespan and increases resistance to oxidative stress [8,9]. These observations were highly suggestive of a close cooperation between Klotho and FGF23 and/or its receptor(s). Others have shown that FGF23 binds to multiple FGF receptors (FGFRs) [10]. Table 1 provides a summary of the presently known role of Klotho in numerous systemic and organ functions and of the biochemical expression of, respectively, its absence and its overfunction in animal models and in man.


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  		Table 1. Multiple functions of Klotho in health and disease

 
Of note, Klotho was the topic of a Translational Nephrology article in a recent issue of NDT, with particular focus on its role in the control of calcium homeostasis [11].



   Regulation of FGF23 signalling by Klotho
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 Why is Klotho of...
 Regulation of FGF23 signalling...
Conversion by Klotho of...
 Conclusion
 References
 
The common phenotypes of Klotho and FGF23 over-expression and deletion, respectively, led to the postulate of a common signal transduction pathway. Kurosu et al. [3] showed that Klotho protein directly bound to multiple FGFRs. The Klotho–FGFR complex bound to FGF23 with higher affinity than FGFR or Klotho alone. In addition, Klotho significantly enhanced the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK in various types of cells. Very recently, Urakawa et al. [12] made an important further contribution to our understanding of this interaction. They reasoned that the renotropic activity of circulating FGF23 was compatible with the presence of a unique, FGF23-specific receptor in the kidney. In order to prove their hypothesis, they chose different experimental approaches in vitro and in vivo.



   Conversion by Klotho of canonical FGF receptor into FGF23-specific receptor
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 Why is Klotho of...
 Regulation of FGF23 signalling...
 Conversion by Klotho of...
Conclusion
 References
 
Over-expression of FGF23 in animals and in humans does not reproduce the effects of other FGF molecules, suggesting the existence of a specific FGF receptor (FGFR) for FGF23. Although 22 different FGF molecules have been identified to date, only four genes encode FGFRs with a few additional isoforms by alternative RNA splicing. This suggests that co-receptors could modulate FGFR affinity for the various FGFs. Several lines of evidence support the role of Klotho as one of these co-receptors.

First, Urakawa et al. [12] forced the expression of Klotho respectively in ovary cells and renal cells, which are normally devoid of Klotho. This enabled high affinity binding of FGF23 to the cell surface and made the cells responsive to FGF23 treatment, as demonstrated by the activation of FGF23-dependent post-receptor events, such as the phosphorylation of extracellular signal-regulated kinase (ERK) protein and enhanced mRNA and protein expression of the gene early growth-responsive 1 (Egr-1).

Second, the serum concentration of FGF23 in Klotho-deficient mice was 2000 times higher than in wild-type mice, and they did not respond to pharmacological doses of exogenous FGF23.

Third, an anti-Klotho monoclonal antibody specifically antagonized FGF23 effects in vitro, in Klotho-expressing cells, and in vivo in mice, despite an increase in circulating FGF23 concentration. Although Kurosu et al. recently showed, by immunoprecipitation experiments, that Klotho can bind to various FGFRs [3], the results by Urokawa et al. suggest that Klotho specifically interacts with the FGFR1(IIIc) subtype. Coexpression of Klotho with FGFR1(IIIc) in various cell lines specifically enabled FGF23 signalling. Furthermore the addition of heparin stabilized the FGF23-FGFR1(IIIc)-Klotho complex but did not substitute for Klotho. Figure 2 provides a schematic view of the interaction between FGF23, Klotho and its receptor.


Figure 2
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  		Fig. 2. Schematic view of the interaction between FGF23, Klotho and their receptor, FGFR1(IIIc).

 


   Conclusion
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 Why is Klotho of...
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References
 
The mystery of the synergy between Klotho, FGF23 and its receptor has been progressively unravelled. The recent demonstration, that Klotho transforms one of the canonical receptors for various FGFs, namely FGFR1(IIIc), into a specific receptor for FGF23, is a major breakthrough. It is still uncertain, however, whether this effect of Klotho is strictly limited to this FGFR subtype. The unique biological activity of FGF23 in the kidney appears to depend on the limited local availability of Klotho. However, in the kidney, FGF23 effects are mainly observed in the proximal tubule, while Klotho expression is limited to the distal tubule.

From a more general point of view, the discovery of the conversion by Klotho of a non-specific to a specific FGF receptor may apply to other FGF-FGF receptor systems. As pointed out by Urakawa et al. [12], this form of conversion may represent a new type of receptor modulation and illustrates the potential diversity of biological responses in the presence of similar, and apparently redundant ligand and receptor subtypes.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Urakawa, I, Yamazaki, Y, Shimada, T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444: 770–774. Back



   References
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 Why is Klotho of...
 Regulation of FGF23 signalling...
 Conversion by Klotho of...
 Conclusion
 References
 

  1. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature (1997) 390:45–51.[CrossRef][Medline]
  2. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun (1998) 242:626–630.[CrossRef][ISI][Medline]
  3. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem (2006) 281:6120–6123.[Abstract/Free Full Text]
  4. Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science (2005) 310:490–493.[Abstract/Free Full Text]
  5. Yoshida T, Fujimori T, Nabeshima Y. Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology (2002) 143:683–689.[Abstract/Free Full Text]
  6. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest (2004) 113:561–568.[CrossRef][ISI][Medline]
  7. Sitara D, Razzaque MS, Hesse M, et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol (2004) 23:421–432.[CrossRef][ISI][Medline]
  8. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science (2005) 309:1829–1833.[Abstract/Free Full Text]
  9. Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem (2005) 280:38029–38034.[Abstract/Free Full Text]
  10. Yu X, Ibrahimi OA, Goetz R, et al. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology (2005) 146:4647–4656.[Abstract/Free Full Text]
  11. Lewin E, Olgaard K. Klotho, an important new factor for the activity of Ca2+ channels, connecting calcium homeostasis, ageing and uraemia. Nephrol Dial Transplant (2006) 21:1770–1772.[Free Full Text]
  12. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature (2006) 444:770–774.[CrossRef][Medline]
Received for publication: 29. 1.07
Accepted in revised form: 12. 2.07


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