Abstract
Klotho and fibroblast growth factor 1 (FGFR1) are expressed not only in FGF23’s classical target organ, the kidney, but also in other organs such as the parathyroid. FGF23 acts on the parathyroid to decrease PTH mRNA and serum PTH levels. It does this by activating the MAPK pathway. In chronic kidney disease there are very high levels of serum FGF23 together with increased serum PTH levels, implying resistance of the parathyroid to the action of FGF23. This has been shown in parathyroid tissue surgically removed from dialysis patients as well as in experimental models of uremia to be due to down-regulation of klotho-FGFR1 expression in the parathyroid. Moreover, the parathyroids of rats with advanced uremia do not respond to administered FGF23 by activation of the MAPK pathway or inhibition of PTH secretion. Therefore, there is down-regulation of parathyroid klotho-FGFR1 in CKD which correlates with the resistance of the parathyroid to FGF23. A further subject of great interest in this field is the effect of PTH to directly increase FGF23 expression by osteoblast like cells in culture and the observations that parathyroidectomy prevents and corrects the increased serum FGF23 level of experimental CKD as well as decreases FGF23 in patients with CKD. There is therefore a negative feedback loop between bone and the parathyroid.
This is a preview of subscription content, log in via an institution to check access.
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
White KE, Evans WE, O’Riordan JLH et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26(3):345–348.
Shimada T, Mizutani S, Muto T et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98(11):6500–6505.
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(3):429–435.
Kurosu H, Ogawa Y, Miyoshi M et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281(10):6120–6123.
Araya K, Fukumoto S, Backenroth R et al. A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 2005; 90(10):5523–5527.
Kuro-o M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 2006; 15(4):437–441.
Farrow EG, Davis SI, Summers LJ et al. Initial FGF23-Mediated Signaling Occurs in the Distal Convoluted Tubule. J Am Soc Nephrol 2009; 20(5):955–960.
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(14):1776–1782.
Urakawa I, Yamazaki Y, Shimada T et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444(7120):770–774.
White KE, Jonsson KB, Carn G et al. The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab 2001; 86(2):497–500.
Shimada T, Urakawa I, Yamazaki Y et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004; 314(2):409–414.
Bai XY, Miao D, Goltzman D et al. The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 2003; 278(11):9843–9849.
Bai X, Miao D, Li J et al. Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinol 2004; 145(11):5269–5279.
Larsson T, Marsell R, Schipani E et al. Transgenic mice expressing Fibroblast Growth Factor 23 under the control of the (alpha)1(I) collagen promoter exhibit growth retardation, osteomalacia and disturbed phosphate homeostasis. Endocrinol 2004; 145:3087–3094.
Ben Dov IZ, Galitzer H, Lavi-Moshayoff V et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007; 117(12):4003–4008.
Goetz R, Beenken A, Ibrahimi OA et al. Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of FGF19 Subfamily Members. Mol Cell Biol 2007; 27(9):3417–3428.
Yamashita T, Konishi M, Miyake A. Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway. J Biol Chem 2002; 277(31):28265–28270.
Krajisnik T, Bjorklund P, Marsell R et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 2007; 195(1):125–131.
Lavi-Moshayoff V, Silver J, Naveh-Many T. Human PTH gene regulation in vivo using transgenic mice. Am J Physiol Renal Physiol 2009; 297(3):F713–F719.
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(9):1509–1518.
Imanishi Y, Inaba M, Nakatsuka K et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 2004; 65(5):1943–1946.
Isakova T, Gutierrez O, Shah A et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 2008; 19(3):615–623.
Westerberg PA, Linde T, Wikstrom B. Regulation of fibroblast growth factor-23 in chronic kidney disease. Nephrol Dial Transplant 2007; 22(11):3202–3207.
Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH, calcium and phosphorus in patients with chronic kidney disease: Results of the study to evaluate early kidney disease. Kidney Int 2007; 71(1):31–38.
Silver J, Kilav R, Naveh-Many T. Mechanisms of secondary hyperparathyroidism. Am J Physiol Renal Physiol 2002; 283(3):F367–F376.
Meir T, Levi R, Lieben L et al. Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the VDR in parathyroid physiology. Am J Physiol Renal Physiol 2009.
Gutierrez O, Isakova T, Rhee E et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16(7):2205–2215.
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(9):2600–2608.
Nakanishi S, Kazama JJ, Nii-Kono T et al. Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. Kidney Int 2005; 67(3):1171–1178.
Gutierrez OM, Mannstadt M, Isakova T et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359(6):584–592.
Galitzer H, Ben-Dov IZ, Silver J, Naveh-Many T. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 2010; 77(3):211–218.
Komaba H, Goto S, Fujii H et al. Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney Int 2009.
Komaba H, Fukagawa M. FGF23-parathyroid interaction: implications in chronic kidney disease. Kidney Int 2009.
Kawata T, Imanishi Y, Kobayashi K et al. Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. J Am Soc Nephrol 2007; 18(10):2683–2688.
Brown WW, Juppner H, Langman CB et al. Hypophosphatemia with elevations in serum FGF23 in a child with Jansen’s Metaphyseal Chondrodysplasia (FGF23 in Jansen’s Syndrome). J Clin Endocrinol Metab 2008.
Shimada T, Yamazaki Y, Takahashi M et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 2005; 289(5):F1088–F1095.
Canalejo R, Canalejo A, Martinez-Moreno JM et al. FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol 2010; 21(7):1125–1135.
Lavi-Moshayoff V, Wasserman G, Meir T et al. PTH increases FGF23 gene expression and mediates the high FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. AM J Physio Renal Physiol 2010; 299(4):F882–9.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Silver, J., Naveh-Many, T. (2012). FGF23 and the Parathyroid. 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_6
Download citation
DOI: https://doi.org/10.1007/978-1-4614-0887-1_6
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)