Abstract
The molecular interactions of fibroblast growth factor 23 (FGF23), klotho and vitamin D coordinate to regulate the delicate phosphate levels of the body. Vitamin D can induce both FGF23 and klotho synthesis to influence renal phosphate balance. In the presence of klotho, FGF23 protein gains bioactivity to influence systemic phosphate homeostasis. Experimental studies have convincingly shown that in the absence of klotho, FGF23 is unable to regulate in vivo phosphate homeostasis. Furthermore, genetic inactivation of FGF23, klotho or both of the genes have resulted in markedly increased renal expression of 1-alpha hydroxylase [1α(OH)ase] and concomitant elevated serum levels of 1,25, dihydroxyvitamin D [1,25(OH)2D] in the mutant mice. Vitamin D can induce the expression of both FGF23 and klotho while, FGF23 can suppress renal expression of 1α(OH)ase to reduce 1,25(OH)2D activity. In this brief chapter, I will summarize the possible in vivo interactions of FGF23, klotho and vitamin D, in the light of recent mouse genetics studies.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Rastegar A. New concepts in pathogenesis of renal hypophosphatemic syndromes. Iran J Kidney Dis 2009;3:1–6.
Gaasbeek A, Meinders AE. Hypophosphatemia: an update on its etiology and treatment. Am J Med 2005; 118:1094–101.
Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 2007; 69:341–59.
Imel EA, Econs MJ. Fibroblast growth factor 23: roles in health and disease. J Am Soc Nephrol 2005; 16:2565–75.
Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008; 118:3820–8.
Forster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate: A molecular perspective. Kidney Int 2006; 70:1548–59.
Nabeshima Y, Imura H. alpha-Klotho: a regulator that integrates calcium homeostasis. Am J Nephrol 2008; 28:455–64.
Razzaque MS. Klotho and Na+,K+-ATPase activity: solving the calcium metabolism dilemma? Nephrol Dial Transplant 2008; 23:459–61.
Imura A, Tsuji Y, Murata M et al. alpha-Klotho as a regulator of calcium homeostasis. Science 2007; 316:1615–8.
Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 2000; 277:494–8.
ADHR_Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR Consortium. Nat Genet 2000; 26:345–8.
Shimada T, Hasegawa H, Yamazaki Y et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19:429–35.
Larsson T, Marsell R, Schipani E et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia and disturbed phosphate homeostasis. Endocrinology 2004; 145:3087–94.
DeLuca S, Sitara D, Kang K et al. Amelioration of the premature aging-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23. J Pathol 2008; 216:345–355.
Benet-Pages A, Orlik P, Strom TM et al. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 2005; 14:385–90.
Imanishi Y, Inaba M, Nakatsuka K et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 2004; 65:1943–6.
Nishi H, Nii-Kono T, Nakanishi S et al. Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients with secondary hyperparathyroidism. Nephron Clin Pract 2005; 101:c94–9.
Saito H, Maeda A, Ohtomo S et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 2005; 280:2543–9.
Shigematsu T, Kazama JJ, Yamashita T et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 2004; 44:250–6.
Fliser D, Kollerits B, Neyer U et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007; 18:2600–8.
Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci 2009; 337:116–22.
Gutierrez OM, Januzzi JL, Isakova T et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119:2545–52.
Kuro-o M. Klotho in chronic kidney disease—what’s new? Nephrol Dial Transplant 2009; 24:1705–8.
Razzaque MS. Does FGF23 toxicity influence the outcome of chronic kidney disease? Nephrol Dial Transplant 2009; 24:4–7.
Lanske B, Razzaque MS. Mineral metabolism and aging: the fibroblast growth factor 23 enigma. Curr Opin Nephrol Hypertens 2007; 16:311–8.
Lanske B, Razzaque MS. Premature aging in klotho mutant mice: cause or consequence? Ageing Res Rev 2007; 6:73–9.
Takeshita K, Fujimori T, Kurotaki Y et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 2004; 109:1776–82.
Chen CD, Podvin S, Gillespie E et al. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 2007; 104:19796–801.
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.
Mohammadi M, Olsen SK, Ibrahimi OA. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 2005; 16:107–37.
Kurosu H, Ogawa Y, Miyoshi M et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281:6120–3.
Urakawa I, Yamazaki Y, Shimada T et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770–4.
Gattineni J, Bates C, Twombley K et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297(2):F282–91.
Liu S, Vierthaler L, Tang W et al. FGFR3 and FGFR4 do not mediate renal effects of FGF23. J Am Soc Nephrol 2008; 19:2342–50.
Medici D, Razzaque MS, Deluca S et al. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. J Cell Biol 2008; 182:459–65.
Goetz R, Beenken A, Ibrahimi OA et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007; 27:3417–28.
Yamazaki Y, Tamada T, Kasai N et al. Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res 2008; 23:1509–18.
Kuro-o M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 2006; 15:437–41.
Nakatani T, Ohnishi M, Razzaque MS. Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J 2009; 23:3702–11.
Nakatani T, Bara S, Ohnishi M et al. In vivo genetic evidence of klotho-dependent functions of FGF23 in regulation of systemic phosphate homeostasis. FASEB J 2009; 23:433–41.
Razzaque MS. FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player? Am J Physiol Renal Physiol 2009; 296:F470–6.
Razzaque MS, Lanske B. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J Endocrinol 2007; 194:1–10.
Bai X, Dinghong Q, Miao D et al. Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype. Am J Physiol Endocrinol Metab 2009; 296:E79–88.
Ichikawa S, Imel EA, Kreiter ML et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 2007; 117:2684–91.
Lanske B, Razzaque MS. Vitamin D and aging: old concepts and new insights. J Nutr Biochem 2007; 18:771–7.
Ohnishi M, Nakatani T, Lanske B et al. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 2009; 75:1166–72.
Tsujikawa H, Kurotaki Y, Fujimori T et al. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003; 17:2393–403.
Memon F, El-Abbadi M, Nakatani T et al. Does Fgf23-klotho activity influence vascular and soft tissue calcification through regulating mineral ion metabolism? Kidney Int 2008; 74:566–70.
Ohnishi M, Nakatani T, Lanske B et al. In vivo genetic evidence for suppressing vascular and soft tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1,25-dihydroxyvitamin-D levels. Circ Cardiovasc Genet 2009; 2:583–90.
Liu S, Tang W, Zhou J et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 2006; 17:1305–15.
Razzaque MS. Can fibroblast growth factor 23 fine-tune therapies for diseases of abnormal mineral ion metabolism? Nat Clin Pract Endocrinol Metab 2007; 3:788–9.
Razzaque MS. The FGF23 Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 2009; 5:611–19.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Razzaque, M.S. (2012). FGF23, Klotho and Vitamin D Interactions:. In: Kuro-o, M. (eds) Endocrine FGFs and Klothos. Advances in Experimental Medicine and Biology, vol 728. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0887-1_5
Download citation
DOI: https://doi.org/10.1007/978-1-4614-0887-1_5
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-0886-4
Online ISBN: 978-1-4614-0887-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)