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Published in: Calcified Tissue International 1/2018

Open Access 01-01-2018 | Original Research

Fibroblast Growth Factor (FGF) 23 Regulates the Plasma Levels of Parathyroid Hormone In Vivo Through the FGF Receptor in Normocalcemia, But Not in Hypocalcemia

Authors: Maria L. Mace, Eva Gravesen, Anders Nordholm, Klaus Olgaard, Ewa Lewin

Published in: Calcified Tissue International | Issue 1/2018

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Abstract

The calcium and phosphate homeostasis is regulated by a complex interplay between parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and calcitriol. Experimental studies have demonstrated an inhibitory effect of FG23 on PTH production and secretion; the physiological role of this regulation is however not well understood. Surprisingly, in uremia, concomitantly elevated FGF23 and PTH levels are observed. The parathyroid gland rapidly loses its responsiveness to extracellular calcium in vitro and a functional parathyroid cell line has currently not been established. Therefore, the aim of the present investigation was to study the impact of FGF23 on the Ca2+/PTH relationship in vivo under conditions of normocalcemia and hypocalcemia. Wistar rats were allocated to treatment with intravenous recombinant FGF23 and inhibition of the FGF receptor in the setting of normocalcemia and acute hypocalcemia. We demonstrated that FGF23 rapidly inhibited PTH secretion and that this effect was completely blocked by inhibition of the FGF receptor. Furthermore, inhibition of the FGF receptor by itself significantly increased PTH levels, indicating that FGF23 has a suppressive tonus on the parathyroid gland’s PTH secretion. In acute hypocalcemia, there was no effect of either recombinant FGF23 or FGF receptor inhibition on the physiological response to the low ionized calcium levels. In conclusion, FGF23 has an inhibitory tonus on PTH secretion in normocalcemia and signals through the FGF receptor. In acute hypocalcemia, when increased PTH secretion is needed to restore the calcium homeostasis, this inhibitory effect of FGF23 is abolished.
Literature
1.
go back to reference Lewin E (2004) Parathyroid hormone regulation in normal and uremic rats. Reversibility of secondary hyperparathyroidism after experimental kidney transplantation. Dan Med Bull 51:184–206PubMed Lewin E (2004) Parathyroid hormone regulation in normal and uremic rats. Reversibility of secondary hyperparathyroidism after experimental kidney transplantation. Dan Med Bull 51:184–206PubMed
2.
go back to reference Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366:575–580CrossRefPubMed Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366:575–580CrossRefPubMed
4.
go back to reference Lewin E, Nielsen PK, Olgaard K (1995) The calcium/parathyroid hormone concept of the parathyroid glands. Curr Opin Nephrol Hypertens 4:324–333CrossRefPubMed Lewin E, Nielsen PK, Olgaard K (1995) The calcium/parathyroid hormone concept of the parathyroid glands. Curr Opin Nephrol Hypertens 4:324–333CrossRefPubMed
5.
go back to reference Huan J, Olgaard K, Nielsen LB, Lewin E (2006) Parathyroid hormone 7–84 induces hypocalcemia and inhibits the parathyroid hormone 1–84 secretory response to hypocalcemia in rats with intact parathyroid glands. J Am Soc Nephrol 17:1923–1930CrossRefPubMed Huan J, Olgaard K, Nielsen LB, Lewin E (2006) Parathyroid hormone 7–84 induces hypocalcemia and inhibits the parathyroid hormone 1–84 secretory response to hypocalcemia in rats with intact parathyroid glands. J Am Soc Nephrol 17:1923–1930CrossRefPubMed
6.
go back to reference Zhang C, Miller CL, Gorkhali R, Zou J, Huang K, Brown EM, Yang JJ (2016) Molecular basis of the extracellular ligands mediated signaling by the calcium sensing receptor. Front Physiol 7:441PubMedPubMedCentral Zhang C, Miller CL, Gorkhali R, Zou J, Huang K, Brown EM, Yang JJ (2016) Molecular basis of the extracellular ligands mediated signaling by the calcium sensing receptor. Front Physiol 7:441PubMedPubMedCentral
7.
go back to reference Geng Y, Mosyak L, Kurinov I, Zuo H, Sturchler E, Cheng TC, Subramanyam P, Brown AP, Brennan SC, Mun HC, Bush M, Chen Y, Nguyen TX, Cao B, Chang DD, Quick M, Conigrave AD, Colecraft HM, McDonald P, Fan QR (2016) Structural mechanism of ligand activation in human calcium-sensing receptor. Elife. doi:10.7554/eLife.3662 PubMedPubMedCentral Geng Y, Mosyak L, Kurinov I, Zuo H, Sturchler E, Cheng TC, Subramanyam P, Brown AP, Brennan SC, Mun HC, Bush M, Chen Y, Nguyen TX, Cao B, Chang DD, Quick M, Conigrave AD, Colecraft HM, McDonald P, Fan QR (2016) Structural mechanism of ligand activation in human calcium-sensing receptor. Elife. doi:10.​7554/​eLife.​3662 PubMedPubMedCentral
9.
go back to reference Nielsen PK, Feldt-Rasmussen U, Olgaard K (1996) A direct effect in vitro of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed parathyroid cells. Nephrol Dial Transplant 11:1762–1768CrossRefPubMed Nielsen PK, Feldt-Rasmussen U, Olgaard K (1996) A direct effect in vitro of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed parathyroid cells. Nephrol Dial Transplant 11:1762–1768CrossRefPubMed
10.
go back to reference Naveh-Many T, Rahamimov R, Livni N, Silver J (1995) Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Investig 96:1786–1793CrossRefPubMedPubMedCentral Naveh-Many T, Rahamimov R, Livni N, Silver J (1995) Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Investig 96:1786–1793CrossRefPubMedPubMedCentral
11.
go back to reference Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123CrossRefPubMedPubMedCentral Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123CrossRefPubMedPubMedCentral
12.
go back to reference Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Investig 117:4003–4008PubMedPubMedCentral Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Investig 117:4003–4008PubMedPubMedCentral
13.
go back to reference Hofman-Bang J, Martuseviciene G, Santini MA, Olgaard K, Lewin E (2010) Increased parathyroid expression of klotho in uremic rats. Kidney Int 78:1119–1127CrossRefPubMed Hofman-Bang J, Martuseviciene G, Santini MA, Olgaard K, Lewin E (2010) Increased parathyroid expression of klotho in uremic rats. Kidney Int 78:1119–1127CrossRefPubMed
14.
go back to reference Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, Westin G, Larsson TE (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131CrossRefPubMed Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, Westin G, Larsson TE (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131CrossRefPubMed
15.
go back to reference Kawakami K, Takeshita A, Furushima K, Miyajima M, Hatamura I, Kuro O, Furuta Y, Sakaguchi K (2017) Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease. Sci Rep. doi:10.1038/srep40534 Kawakami K, Takeshita A, Furushima K, Miyajima M, Hatamura I, Kuro O, Furuta Y, Sakaguchi K (2017) Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease. Sci Rep. doi:10.​1038/​srep40534
16.
go back to reference Komaba H, Fukagawa M (2010) FGF23-parathyroid interaction: implications in chronic kidney disease. Kidney Int 77:292–298CrossRefPubMed Komaba H, Fukagawa M (2010) FGF23-parathyroid interaction: implications in chronic kidney disease. Kidney Int 77:292–298CrossRefPubMed
17.
go back to reference Mithal A, Kifor O, Kifor I, Vassilev P, Butters R, Krapcho K, Simin R, Fuller F, Hebert SC, Brown EM (1995) The reduced responsiveness of cultured bovine parathyroid cells to extracellular Ca2+ is associated with marked reduction in the expression of extracellular Ca(2+)-sensing receptor messenger ribonucleic acid and protein. Endocrinology 136:3087–3092CrossRefPubMed Mithal A, Kifor O, Kifor I, Vassilev P, Butters R, Krapcho K, Simin R, Fuller F, Hebert SC, Brown EM (1995) The reduced responsiveness of cultured bovine parathyroid cells to extracellular Ca2+ is associated with marked reduction in the expression of extracellular Ca(2+)-sensing receptor messenger ribonucleic acid and protein. Endocrinology 136:3087–3092CrossRefPubMed
18.
go back to reference Brown AJ, Zhong M, Ritter C, Brown EM, Slatopolsky E (1995) Loss of calcium responsiveness in cultured bovine parathyroid cells is associated with decreased calcium receptor expression. Biochem Biophys Res Commun 212:861–867CrossRefPubMed Brown AJ, Zhong M, Ritter C, Brown EM, Slatopolsky E (1995) Loss of calcium responsiveness in cultured bovine parathyroid cells is associated with decreased calcium receptor expression. Biochem Biophys Res Commun 212:861–867CrossRefPubMed
19.
go back to reference Nordholm A, Mace ML, Gravesen E, Olgaard K, Lewin E (2015) A potential kidney-bone axis involved in the rapid minute-to-minute regulation of plasma Ca2+. BMC Nephrol 16:29CrossRefPubMedPubMedCentral Nordholm A, Mace ML, Gravesen E, Olgaard K, Lewin E (2015) A potential kidney-bone axis involved in the rapid minute-to-minute regulation of plasma Ca2+. BMC Nephrol 16:29CrossRefPubMedPubMedCentral
20.
go back to reference Mace ML, Gravesen E, Hofman-Bang J, Olgaard K, Lewin E (2015) Key role of the kidney in the regulation of fibroblast growth factor 23. Kidney Int 88:1304–1313CrossRefPubMed Mace ML, Gravesen E, Hofman-Bang J, Olgaard K, Lewin E (2015) Key role of the kidney in the regulation of fibroblast growth factor 23. Kidney Int 88:1304–1313CrossRefPubMed
21.
go back to reference Canalejo R, Canalejo A, Martinez-Moreno JM, Rodriguez-Ortiz ME, Estepa JC, Mendoza FJ, Munoz-Castaneda JR, Shalhoub V, Almaden Y, Rodriguez M (2010) FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol 21:1125–1135CrossRefPubMedPubMedCentral Canalejo R, Canalejo A, Martinez-Moreno JM, Rodriguez-Ortiz ME, Estepa JC, Mendoza FJ, Munoz-Castaneda JR, Shalhoub V, Almaden Y, Rodriguez M (2010) FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol 21:1125–1135CrossRefPubMedPubMedCentral
23.
go back to reference Laestander C, Engstrom W (2014) Role of fibroblast growth factors in elicitation of cell responses. Cell Prolif 47:3–11CrossRefPubMed Laestander C, Engstrom W (2014) Role of fibroblast growth factors in elicitation of cell responses. Cell Prolif 47:3–11CrossRefPubMed
24.
go back to reference Touchberry CD, Green TM, Tchikrizov V, Mannix JE, Mao TF, Carney BW, Girgis M, Vincent RJ, Wetmore LA, Dawn B, Bonewald LF, Stubbs JR, Wacker MJ (2013) FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab 304:E863–E873CrossRefPubMedPubMedCentral Touchberry CD, Green TM, Tchikrizov V, Mannix JE, Mao TF, Carney BW, Girgis M, Vincent RJ, Wetmore LA, Dawn B, Bonewald LF, Stubbs JR, Wacker MJ (2013) FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab 304:E863–E873CrossRefPubMedPubMedCentral
25.
go back to reference Olauson H, Lindberg K, Amin R, Sato T, Jia T, Goetz R, Mohammadi M, Andersson G, Lanske B, Larsson TE (2013) Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 9:e1003975CrossRefPubMedPubMedCentral Olauson H, Lindberg K, Amin R, Sato T, Jia T, Goetz R, Mohammadi M, Andersson G, Lanske B, Larsson TE (2013) Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 9:e1003975CrossRefPubMedPubMedCentral
26.
go back to reference Mace ML, Gravesen E, Nordholm A, Hofman-Bang J, Secher T, Olgaard K, Lewin E (2017) Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia. Kidney Int 92:165–178CrossRefPubMed Mace ML, Gravesen E, Nordholm A, Hofman-Bang J, Secher T, Olgaard K, Lewin E (2017) Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia. Kidney Int 92:165–178CrossRefPubMed
27.
go back to reference Galitzer H, Ben-Dov IZ, Silver J, Naveh-Many T (2010) Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 77:211–218CrossRefPubMed Galitzer H, Ben-Dov IZ, Silver J, Naveh-Many T (2010) Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 77:211–218CrossRefPubMed
28.
go back to reference Kumata C, Mizobuchi M, Ogata H, Koiwa F, Nakazawa A, Kondo F, Kadokura Y, Kinugasa E, Akizawa T (2010) Involvement of alpha-klotho and fibroblast growth factor receptor in the development of secondary hyperparathyroidism. Am J Nephrol 31:230–238CrossRefPubMed Kumata C, Mizobuchi M, Ogata H, Koiwa F, Nakazawa A, Kondo F, Kadokura Y, Kinugasa E, Akizawa T (2010) Involvement of alpha-klotho and fibroblast growth factor receptor in the development of secondary hyperparathyroidism. Am J Nephrol 31:230–238CrossRefPubMed
29.
go back to reference Ohkido I, Yokoyama K, Imura A, Utsunomiya Y, Hosoya T, Nabeshima Y (2010) Persistent alpha-Klotho (a-Kl) expression in the parathyroid glands of patients with secondary hyperparathyroidism. Nephrol Dial Transplant 25:1007–1008CrossRefPubMed Ohkido I, Yokoyama K, Imura A, Utsunomiya Y, Hosoya T, Nabeshima Y (2010) Persistent alpha-Klotho (a-Kl) expression in the parathyroid glands of patients with secondary hyperparathyroidism. Nephrol Dial Transplant 25:1007–1008CrossRefPubMed
30.
go back to reference Naveh-Many T, Silver J (1990) Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat. J Clin Investig 86:1313–1319CrossRefPubMedPubMedCentral Naveh-Many T, Silver J (1990) Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat. J Clin Investig 86:1313–1319CrossRefPubMedPubMedCentral
31.
go back to reference Sela-Brown A, Russell J, Koszewski NJ, Michalak M, Naveh-Many T, Silver J (1998) Calreticulin inhibits vitamin D’s action on the PTH gene in vitro and may prevent vitamin D’s effect in vivo in hypocalcemic rats. Mol Endocrinol 12:1193–1200PubMed Sela-Brown A, Russell J, Koszewski NJ, Michalak M, Naveh-Many T, Silver J (1998) Calreticulin inhibits vitamin D’s action on the PTH gene in vitro and may prevent vitamin D’s effect in vivo in hypocalcemic rats. Mol Endocrinol 12:1193–1200PubMed
33.
go back to reference Rodriguez-Ortiz ME, Lopez I, Munoz-Castaneda JR, Martinez-Moreno JM, Ramirez AP, Pineda C, Canalejo A, Jaeger P, Aguilera-Tejero E, Rodriguez M, Felsenfeld A, Almaden Y (2012) Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol 23:1190–1197CrossRefPubMedPubMedCentral Rodriguez-Ortiz ME, Lopez I, Munoz-Castaneda JR, Martinez-Moreno JM, Ramirez AP, Pineda C, Canalejo A, Jaeger P, Aguilera-Tejero E, Rodriguez M, Felsenfeld A, Almaden Y (2012) Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol 23:1190–1197CrossRefPubMedPubMedCentral
34.
go back to reference Gravesen E, Mace ML, Hofman-Bang J, Olgaard K, Lewin E (2014) Circulating FGF23 levels in response to acute changes in plasma Ca(2+). Calcif Tissue Int 95:46–53CrossRefPubMed Gravesen E, Mace ML, Hofman-Bang J, Olgaard K, Lewin E (2014) Circulating FGF23 levels in response to acute changes in plasma Ca(2+). Calcif Tissue Int 95:46–53CrossRefPubMed
35.
go back to reference Patstone G, Maher P (1996) Copper and calcium binding motifs in the extracellular domains of fibroblast growth factor receptors. J Biol Chem 271:3343–3346CrossRefPubMed Patstone G, Maher P (1996) Copper and calcium binding motifs in the extracellular domains of fibroblast growth factor receptors. J Biol Chem 271:3343–3346CrossRefPubMed
36.
go back to reference Takagi Y, Shrivastav S, Miki T, Sakaguchi K (1994) Molecular cloning and expression of the acidic fibroblast growth factor receptors in a rat parathyroid cell line (PT-r). Parathyroid cell-specific calcium-dependent change of ligand accessibility and covalent attachment of heparan sulfate glycosaminoglycan to the receptors. J Biol Chem 269:23743–23749PubMed Takagi Y, Shrivastav S, Miki T, Sakaguchi K (1994) Molecular cloning and expression of the acidic fibroblast growth factor receptors in a rat parathyroid cell line (PT-r). Parathyroid cell-specific calcium-dependent change of ligand accessibility and covalent attachment of heparan sulfate glycosaminoglycan to the receptors. J Biol Chem 269:23743–23749PubMed
37.
go back to reference Kawata T, Imanishi Y, Kobayashi K, Miki T, Arnold A, Inaba M, Nishizawa Y (2007) Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. J Am Soc Nephrol 18:2683–2688CrossRefPubMed Kawata T, Imanishi Y, Kobayashi K, Miki T, Arnold A, Inaba M, Nishizawa Y (2007) Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. J Am Soc Nephrol 18:2683–2688CrossRefPubMed
38.
go back to reference Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T (2010) PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 299:F882–F889CrossRefPubMed Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T (2010) PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 299:F882–F889CrossRefPubMed
39.
go back to reference Meir T, Durlacher K, Pan Z, Amir G, Richards WG, Silver J, Naveh-Many T (2014) Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription. Kidney Int 86:1106–1115CrossRefPubMed Meir T, Durlacher K, Pan Z, Amir G, Richards WG, Silver J, Naveh-Many T (2014) Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription. Kidney Int 86:1106–1115CrossRefPubMed
40.
go back to reference Fan Y, Bi R, Densmore MJ, Sato T, Kobayashi T, Yuan Q, Zhou X, Erben RG, Lanske B (2016) Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. FASEB J 30:428–440CrossRefPubMed Fan Y, Bi R, Densmore MJ, Sato T, Kobayashi T, Yuan Q, Zhou X, Erben RG, Lanske B (2016) Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. FASEB J 30:428–440CrossRefPubMed
Metadata
Title
Fibroblast Growth Factor (FGF) 23 Regulates the Plasma Levels of Parathyroid Hormone In Vivo Through the FGF Receptor in Normocalcemia, But Not in Hypocalcemia
Authors
Maria L. Mace
Eva Gravesen
Anders Nordholm
Klaus Olgaard
Ewa Lewin
Publication date
01-01-2018
Publisher
Springer US
Published in
Calcified Tissue International / Issue 1/2018
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-017-0333-9

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