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FGF23: its role in renal bone disease

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Abstract

Fibroblast growth factor 23 (FGF23) is a recently characterized peptide hormone produced mainly in the bone. It is secreted in response to dietary phosphorus load, and its main function is the promotion of urinary phosphate excretion and the suppression of active vitamin D (1,25D) production in the kidney. As such, FGF23 plays an important role in the maintenance of systemic phosphate homeostasis. In the advanced stages of chronic kidney disease (CKD), the kidney cannot excrete a phosphate load even in the presence of high levels of FGF23. This results in both hyperphosphatemia and a low level of 1,25D that stimulates the secretion of parathyroid hormone (PTH), leading to the development of secondary hyperparathyroidism. In chronic dialysis patients without residual renal function, FGF23 levels become extremely high due to stimulation by vitamin D therapy as well as by high levels of serum phosphate and PTH. Recent investigations have demonstrated that serum FGF23 level can be a useful marker for the prediction of the future development of refractory hyperparathyroidism and the response to vitamin D therapy in dialysis patients. In addition, putative protective roles of FGF23 against calcification have also been speculated on. Further elucidation of the mechanisms of FGF23 action will be needed to understand the various roles of FGF23 in CKD-Mineral and Bone Disorder (CKD-MBD).

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References

  1. Kurokawa K, Fukagawa M (1999) Uremic bone diseases: Advances over the last 30 years. J Nephrol 12 [Suppl 2]:S63–S67

    PubMed  Google Scholar 

  2. Goodman WG, London G, Amann K, Block GA, Giachelli C, Hruska KA, Ketteler M, Levin A, Massy Z, McCarron DA, Raggi P, Shanahan CM, Yorioka N; Vascular calcification work group (2004) Vascular calcification in chronic kidney disease. Am J Kidney Dis 43:572–579

    PubMed  Google Scholar 

  3. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lamiere N, Eknoyan G (2006) Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcome (KDIGO). Kidney Int 69:1945–1953

    CAS  PubMed  Google Scholar 

  4. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 98:6500–6505

    CAS  PubMed  Google Scholar 

  5. Berndt TJ, Schiavi S, Kumar R (2005) “Phosphatonins” and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol 289:F1170–F1182

    CAS  PubMed  Google Scholar 

  6. Imel EA, Econs MJ (2005) Fibroblast growth factor 23: Roles in health and disease. J Am Soc Nephrol 16:2565–2575

    CAS  PubMed  Google Scholar 

  7. Yamazaki Y, Okazaki R, Shimada M, Hasegawa Y, Satoh K, Tajima Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S (2002) Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87:4957–4960

    CAS  PubMed  Google Scholar 

  8. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is a potent regulator of the vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435

    CAS  PubMed  Google Scholar 

  9. Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2004) FGF-23 transgenic mice demonstrate hypophostemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 314:409–414

    CAS  PubMed  Google Scholar 

  10. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Juppner H, Jonsson KB (2004) Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha (I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145:3087–3094

    CAS  PubMed  Google Scholar 

  11. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Miyamoto K, Ito M, Kuwahata M, Kato S, Segawa H (2005) Inhibition of intestinal sodium-dependent inorganic phosphate transport by fibrous growth factor 23. Ther Apher Dial 9:331–335

    CAS  PubMed  Google Scholar 

  13. Mirams M, Robinson BG, Mason RS, Nelson AE (2004) Bone as a source of FGF23: regulation by phosphate? Bone 35:1192–1199

    CAS  PubMed  Google Scholar 

  14. Kobayashi K, Imanishi Y, Koshiyama H, Miyauchi A, Wakasa K, Kawata T, Goto H, Ohashi H, Koyano HM, Mochizuki R, Miki T, Inaba M, Nishizawa Y (2006) Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia. Life Sci 78:2295–2301

    CAS  PubMed  Google Scholar 

  15. Koiwa F, Kazama JJ, Tokumoto A, Onoda N, Kato H, Okada T, Nii-Kono T, Fukagawa M, Shigematsu T (2005) Sevelamer hydrochloride and calcium bicarbonate reduce serum fibroblast growth factor 23 level in dialysis patients. Ther Aphr Dial 9:336–339

    CAS  Google Scholar 

  16. Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M (2006) Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int 69:531–537

    CAS  PubMed  Google Scholar 

  17. Perwad F, Azam N, Zhang MYH, Yamashita T, Tenenhouse HS, Portale AA (2005) Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146:5358–5364

    CAS  PubMed  Google Scholar 

  18. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB (2003) Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64:2272–2279

    CAS  PubMed  Google Scholar 

  19. Ferrari SL, Bonjour JP, Rizzoli R (2005) FGF-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90:1519–1524

    CAS  PubMed  Google Scholar 

  20. Yamashita H, Yamashita T, Miyamoto M, Shigematsu T, Kazama JJ, Shimada T, Yamazaki Y, Fukumoto S, Fukagawa M, Noguchi S (2004) Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. Eur J Endocrinol 151:55–60

    CAS  PubMed  Google Scholar 

  21. Tebben PJ, Singh RJ, Clarke BL, Kumar R (2004) Fibroblast growth factor 23, parathyroid hormone, and 1alpha, 25-dihydroxyvitamin D in surgically treated primary hyperparathyroidism. Mayo Clin Proc 79:1508–1513

    CAS  PubMed  Google Scholar 

  22. Kobayashi K, Imanishi Y, Miyauchi A, Onoda N, Kawata T, Tahara H, Goto H, Miki T, Ishimura E, Sugimoto T, Ishikawa T, Inaba M, Nishizawa Y (2006) Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. Eur J Endocrinol 154:93–99

    CAS  PubMed  Google Scholar 

  23. Silver J, Kilav R, Naveh-Many T (2002) Mechanisms of secondary hyperparathyroidism. Am J Physiol Renal Physiol 283:F367–F376

    CAS  PubMed  Google Scholar 

  24. Slatopolsky E, Caglar S, Gradowska L, Canturbury J, Reiss E, Bricker NS (1972) On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake. Kidney Int 2:147–151

    CAS  PubMed  Google Scholar 

  25. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald PN, Brown AJ (1996) Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97:2534–2540

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Portale AA, Booth BE, Halloran BP, Morris RC Jr (1984) Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73:1580–1589

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Weber TJ, Liu S, Indridason OS, Quarles LD (2003) Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 18:1227–1234

    CAS  PubMed  Google Scholar 

  28. Imanishi Y, Inaba M, Nakatsuka K, Nagasue K, Okuno S, Yoshihara A, Miura M, Miyauchi A, Kobayashi K, Miki T, Shoji T, Ishimura E, Nishizawa Y (2004) FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 65:1046–1943

    Google Scholar 

  29. Ito N, Fukumoto S, Takeuchi Y, Yasuda T, Hasegawa Y, Takemoto F, Tajima T, Dobashi K, Yamazaki Y, Yamashita T, Fujita T (2005) Comparison of two assays for fibroblast growth factor (FGF)-23. J Bone Miner Metab 23:440–453

    Google Scholar 

  30. Shigematsu T, Kazama JJ, Yamashita T, Fukumoto S, Hosoya T, Gejyo F, Fukagawa M (2004) Possible involvement of circulating fibroblast growth factor-23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 44:250–256

    CAS  PubMed  Google Scholar 

  31. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16:2205–2215

    CAS  PubMed  Google Scholar 

  32. Nakanishi S, Kazama JJ, Nii-Kono T, Omori K, Yamashita T, Fukumoto S, Gejyo F, Shigematsu T, Fukagawa M (2005) Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. Kidney Int 67:1171–1178

    CAS  PubMed  Google Scholar 

  33. Kazama JJ, Sato F, Omori K, Hama H, Yamamoto S, Maruyama H, Narita I, Gejyo F, Yamashita T, Fukumoto S, Fukagawa M (2005) Pretreatment serum FGF-23 levels predict the efficacy of calcitriol therapy in dialysis patients. Kidney Int 67:1120–1125

    CAS  PubMed  Google Scholar 

  34. Nishi H, Nii-Kono T, Nakanishi S, Yamazaki Y, Yamashita T, Fukumoto S, Ikeda K, Fujimori A, Fukagawa M (2005) Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients with secondary hyperparathyroidism. Nephron Clin Pract 101: c94–c99

    CAS  PubMed  Google Scholar 

  35. Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, Ogata E, Segawa H, Miyamoto K, Fukushima N (2005) Circulating FGF-23 is regulated by 1alpha, 25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280:2543–2549

    CAS  PubMed  Google Scholar 

  36. Ito M, Sakai Y, Furumoto M, Segawa H, Haito S, Yamanaka S, Nakamura R, Kuwahata M, Miyamoto K (2005) Vitamin D and phosphate regulate fibroblast growth factor-23 in K562 cells. Am J Physiol Endocrinol Metab 288:E110–E1109

    CAS  PubMed  Google Scholar 

  37. Collins MT, Lindsay JR, Jain A, Kelly MH, Cutler CM, Weinstein LS, Liu J, Fedarko NS, Winer KK (2005) Fibroblast growth factor-23 is regulated by 1 alpha, 25-dihydroxyvitamin D. J Bone Miner Res 20:1944–1950

    CAS  PubMed  Google Scholar 

  38. Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK (2005) 1 alpha, 25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in the bone: the final link in a renal-gastrointestinal-skeletal axis that control phosphate transport. Am J Physiol Gastrointest Liver Physiol 289: G1036–G1042

    CAS  PubMed  Google Scholar 

  39. Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD (2006) Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17:1305–1315

    CAS  PubMed  Google Scholar 

  40. Yamazaki Y, Urakawa I, Shimada T, Iijima K, Hasegawa H, Fujita T, Fukumoto S, Yamashita T (2005) Identification of essential molecule responsible for tissue specific FGF23 signaling (abstract). J Am Soc Nephrol 16:64A

    Google Scholar 

  41. London GM, Marchais SJ, Guerin AP, Metivier F (2005) Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia. Curr Opin Nephrol Hypertens 14:525–531

    CAS  PubMed  Google Scholar 

  42. Razzaque MS, St-Arnaud R, Taguchi T, Lanske B (2005) FGF-23, vitamin D and calcification: the unholy triad. Nephrol Dial Transplant 20:2032–2035

    CAS  PubMed  Google Scholar 

  43. Araya K, Fukumoto S, Backenroth R, Takeuchi Y, Nakayama K, Ito N, Yoshii N, Yamazaki Y, Yamashita Y, Silver J, Igarashi T, Fujita T (2005) A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 90:5523–5527

    CAS  PubMed  Google Scholar 

  44. Larsson T, Davis SI, Garringer HJ, Mooney SD, Draman MS, Cullen MJ, White KE (2005) Fibroblast growth factor-23 mutants causing familial tumoral calcinosis are differentially processed. Endocrinology 146:3883–3891

    CAS  PubMed  Google Scholar 

  45. Inaba M, Okuno S, Imanishi Y, Yamada S, Shioi A, Yamakawa T, Ishimura E, Nishizawa Y (2006) Role of fibroblast growth factor-23 in peripheral vascular calcification in non-diabetic and diabetic hemodialysis patients. Osteoporosis Int (In press)

  46. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu M-C, Moe O, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signalling by klotho. J Biol Chem 281:6120–6123

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lewin E, Olgaard K (2006) Klotho, an important new factor for the activity of Ca2+ channels, connecting calcium homeostasis, ageing and uraemia. Nephrol Dial Transplant. (DOI https://doi.org/10.1093/ndt/gfl178)

    Google Scholar 

  48. Yu X, Ibrahimi OA, Goetz R, Zhang F, Davis SI, Garringer HJ, Linhardt RJ, Ornitz DM, Mohammadi M, White KE (2005) Analysis of biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 146:4647–4656

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Nephrology and Dialysis Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Masafumi Fukagawa

  2. Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan

    Junichiro James Kazama

Authors
  1. Masafumi Fukagawa
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  2. Junichiro James Kazama
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Correspondence to Masafumi Fukagawa.

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Fukagawa, M., Kazama, J.J. FGF23: its role in renal bone disease. Pediatr Nephrol 21, 1802–1806 (2006). https://doi.org/10.1007/s00467-006-0230-3

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  • DOI: https://doi.org/10.1007/s00467-006-0230-3

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