Skip to main content
SpringerLink
Log in

Phosphate Metabolism: From Physiology to Toxicity

  • Chapter
  • First Online:
Phosphate Metabolism

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1362))

Abstract

Systemic phosphate homeostasis is tightly controlled by the delicate cross-organ talk among intestine, kidney, bone, and parathyroid glands. The endocrine regulation of phosphate homeostasis is primarily mediated by fibroblast growth factor 23 (FGF23), vitamin D, and parathyroid hormone (PTH). Bone-derived FGF23 acts on the proximal tubular epithelial cells of the kidney to partly maintain the homeostatic balance of the phosphate. FGF23, through binding with its cell surface receptors in the presence of klotho, can activate downstream signaling kinases to reduce the functionality of the sodium-phosphate (NaPi) co-transporters of the kidney to influence the systemic phosphate homeostasis. Given the complexity of molecular regulation of phosphate homeostasis, providing information on all aspects of its homeostatic control in a single volume of a book is an overwhelming task. As the Editor, I have organized the chapters that I believe will provide necessary information on the physiologic regulation and pathologic dysregulation of phosphate in health and diseases. Readers will be able to use this volume as a quick reference for updated information on phosphate metabolism without prior acquaintance with the field.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Osuka S, Razzaque MS (2012) Can features of phosphate toxicity appear in normophosphatemia? J Bone Miner Metab 30:10–18

    Article  CAS  Google Scholar 

  2. Razzaque MS (2009) The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 5:611–619

    Article  CAS  Google Scholar 

  3. Kinoshita Y, Fukumoto S (2018) X-linked hypophosphatemia and FGF23-related Hypophosphatemic diseases: prospect for new treatment. Endocr Rev 39:274–291

    Article  Google Scholar 

  4. Razzaque MS (2009) FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player? Am J Physiol Renal Physiol 296:F470–F476

    Article  CAS  Google Scholar 

  5. Razzaque MS (2013) Phosphate toxicity and vascular mineralization. Contrib Nephrol 180:74–85

    Article  CAS  Google Scholar 

  6. Razzaque MS (2011) The dualistic role of vitamin D in vascular calcifications. Kidney Int 79:708–714

    Article  CAS  Google Scholar 

  7. Ohnishi M, Nakatani T, Lanske B, Razzaque MS (2009) 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 2:583–590

    Article  CAS  Google Scholar 

  8. Memon F, El-Abbadi M, Nakatani T, Taguchi T, Lanske B, Razzaque MS (2008) Does Fgf23-klotho activity influence vascular and soft tissue calcification through regulating mineral ion metabolism? Kidney Int 74:566–570

    Article  CAS  Google Scholar 

  9. Florenzano P, Cipriani C, Roszko KL, Fukumoto S, Collins MT, Minisola S, Pepe J (2020) Approach to patients with hypophosphataemia. Lancet Diabetes Endocrinol 8:163–174

    Article  CAS  Google Scholar 

  10. Lanske B, Razzaque MS (2014) Molecular interactions of FGF23 and PTH in phosphate regulation. Kidney Int 86:1072–1074

    Article  CAS  Google Scholar 

  11. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774

    Article  CAS  Google Scholar 

  12. Razzaque MS (2011) Phosphate toxicity: new insights into an old problem. Clin Sci (Lond) 120:91–97

    Article  CAS  Google Scholar 

  13. Razzaque MS (2012) The role of Klotho in energy metabolism. Nat Rev Endocrinol 8:579–587

    Article  CAS  Google Scholar 

  14. Nakatani T, Ohnishi M, Razzaque MS (2009) 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 23:3702–3711

    Article  CAS  Google Scholar 

  15. Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, Mohammadi M, Lanske B, Razzaque MS (2009) In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis. FASEB J 23:433–441

    Article  CAS  Google Scholar 

  16. Ohnishi M, Nakatani T, Lanske B, Razzaque MS (2009) Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney Int 75:1166–1172

    Article  CAS  Google Scholar 

  17. Breusegem SY, Takahashi H, Giral-Arnal H, Wang X, Jiang T, Verlander JW, Wilson P, Miyazaki-Anzai S, Sutherland E, Caldas Y, Blaine JT, Segawa H, Miyamoto K, Barry NP, Levi M (2009) Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency. Am J Physiol Renal Physiol 297:F350–F361

    Article  CAS  Google Scholar 

  18. Fujii T, Shiozaki Y, Segawa H, Nishiguchi S, Hanazaki A, Noguchi M, Kirino R, Sasaki S, Tanifuji K, Koike M, Yokoyama M, Arima Y, Kaneko I, Tatsumi S, Ito M, Miyamoto KI (2019) Analysis of opossum kidney NaPi-IIc sodium-dependent phosphate transporter to understand Pi handling in human kidney. Clin Exp Nephrol 23:313–324

    Article  CAS  Google Scholar 

  19. Shiozaki Y, Segawa H, Ohnishi S, Ohi A, Ito M, Kaneko I, Kido S, Tatsumi S, Miyamoto K (2015) Relationship between sodium-dependent phosphate transporter (NaPi-IIc) function and cellular vacuole formation in opossum kidney cells. J Med Investig 62:209–218

    Article  Google Scholar 

  20. Uwitonze AM, Razzaque MS (2018) Role of magnesium in vitamin D activation and function. J Am Osteopath Assoc 118:181–189

    Article  Google Scholar 

  21. Uwitonze AM, Rahman S, Ojeh N, Grant WB, Kaur H, Haq A, Razzaque MS (2020) Oral manifestations of magnesium and vitamin D inadequacy. J Steroid Biochem Mol Biol 200:105636

    Article  CAS  Google Scholar 

  22. Lanske B, Razzaque MS (2007) Vitamin D and aging: old concepts and new insights. J Nutr Biochem 18:771–777

    Article  CAS  Google Scholar 

  23. Erem S, Atfi A, Razzaque MS (2019) Anabolic effects of vitamin D and magnesium in aging bone. J Steroid Biochem Mol Biol 193:105400

    Article  CAS  Google Scholar 

  24. Brown RB, Haq A, Stanford CF, Razzaque MS (2015) Vitamin D, phosphate, and vasculotoxicity. Can J Physiol Pharmacol 93:1077–1082

    Article  CAS  Google Scholar 

  25. Akimbekov NS, Digel I, Sherelkhan DK, Lutfor AB, Razzaque MS (2020) Vitamin D and the host-gut microbiome: a brief overview. Acta Histochem Cytochem 53:33–42

    Article  CAS  Google Scholar 

  26. Fukumoto S, Yamashita T (2007) FGF23 is a hormone-regulating phosphate metabolism--unique biological characteristics of FGF23. Bone 40:1190–1195

    Article  CAS  Google Scholar 

  27. Yamazaki Y, Tamada T, Kasai N, Urakawa I, Aono Y, Hasegawa H, Fujita T, Kuroki R, Yamashita T, Fukumoto S, Shimada T (2008) Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23. J Bone Miner Res 23:1509–1518

    Article  CAS  Google Scholar 

  28. Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, Koller A, Nizet V, White KE, Dixon JE (2014) Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A 111:5520–5525

    Article  CAS  Google Scholar 

  29. 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

    Article  CAS  Google Scholar 

  30. Bar L, Feger M, Fajol A, Klotz LO, Zeng S, Lang F, Hocher B, Foller M (2018) Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Proc Natl Acad Sci U S A 115:5804–5809

    Article  Google Scholar 

  31. Bar L, Stournaras C, Lang F, Foller M (2019) Regulation of fibroblast growth factor 23 (FGF23) in health and disease. FEBS Lett 593:1879–1900

    Article  Google Scholar 

  32. Daryadel A, Bettoni C, Haider T, Imenez Silva PH, Schnitzbauer U, Pastor-Arroyo EM, Wenger RH, Gassmann M, Wagner CA (2018) Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men. Pflugers Arch 470:1569–1582

    Article  CAS  Google Scholar 

  33. Farrow EG, Yu X, Summers LJ, Davis SI, Fleet JC, Allen MR, Robling AG, Stayrook KR, Jideonwo V, Magers MJ, Garringer HJ, Vidal R, Chan RJ, Goodwin CB, Hui SL, Peacock M, White KE (2011) Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A 108:E1146–E1155

    Article  CAS  Google Scholar 

  34. Akimbekov NS, Digel I, Sherelkhan DK, Razzaque MS (2022) Vitamin D and phosphate interactions in health and disease. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 37–46

    Google Scholar 

  35. Nakatani S, Nakatani A, Mori K, Emoto M, Inaba M, Razzaque MS (2022) Fibroblast growth factor 23 as regulator of vitamin D metabolism. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 47–54

    Google Scholar 

  36. Razzaque MS (2009) Does FGF23 toxicity influence the outcome of chronic kidney disease? Nephrol Dial Transplant 24:4–7

    Article  Google Scholar 

  37. Takashi Y, Fukumoto S (2022) Phosphate-sensing. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 27–36

    Google Scholar 

  38. Abbasian N, Bevington A, Dylan Burger D (2022) Phosphate & endothelial function: how sensing of elevated inorganic phosphate concentration generates signals in endothelial cells. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 85–98

    Google Scholar 

  39. He P, Mann-Collura O, Fling J, Edara N, Hetz R, Razzaque MS (2021) High phosphate actively induces cytotoxicity by rewiring pro-survival and pro-apoptotic signaling networks in HEK293 and HeLa cells. FASEB J 35:e20997

    CAS  PubMed  Google Scholar 

  40. Lewis E, Seltun F, Razzaque MS, He P (2022) Excessive phosphate-mediated EMT in the context of phosphate toxicity. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 73–84

    Google Scholar 

  41. Hu MC, Moe OW (2022) Phosphate and cellular senescence. Adv Exp Med Biol. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 55–72

    Google Scholar 

  42. Erem S, Osuka S, Razzaque MS (2022) Phosphate burden and inflammation. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 7–14

    Google Scholar 

  43. Michigami T, Yamazaki M, Razzaque MS (2022) Extracellular phosphate, inflammation and cytotoxicity. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 15–26

    Google Scholar 

  44. Erem S, Razzaque MS (2018) Dietary phosphate toxicity: an emerging global health concern. Histochem Cell Biol 150:711–719

    Article  CAS  Google Scholar 

  45. Miyamoto K, Oh J, Razzaque MS (2022) Common dietary sources of natural and artificial phosphorus in food. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 99–106

    Google Scholar 

  46. Leifheit-Nestler M, Vogt I, Haffner D, Richter B (2022) Phosphate is a cardiovascular toxin. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 107–134

    Google Scholar 

  47. Guillot AP, Hood VL, Runge CF, Gennari FJ (1982) The use of magnesium-containing phosphate binders in patients with end-stage renal disease on maintenance hemodialysis. Nephron 30:114–117

    Article  CAS  Google Scholar 

  48. Neven E, De Schutter TM, Dams G, Gundlach K, Steppan S, Buchel J, Passlick-Deetjen J, D’Haese PC, Behets GJ (2014) A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats. PLoS One 9:e107067

    Article  Google Scholar 

  49. De Schutter TM, Behets GJ, Geryl H, Peter ME, Steppan S, Gundlach K, Passlick-Deetjen J, D’Haese PC, Neven E (2013) Effect of a magnesium-based phosphate binder on medial calcification in a rat model of uremia. Kidney Int 83:1109–1117

    Article  Google Scholar 

  50. Bruna RE, Kendra CG, Pontes MH (2022) Coordination of phosphate and magnesium metabolism in bacteria. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 135–150

    Google Scholar 

  51. Razzaque MS (2022) Salivary phosphate as a biomarker for human diseases. FASEB Bioadv 4:102–108. https://doi.org/10.1096/fba.2021-00104

  52. Hetz R, Beeler E, Janoczkin A, Kiers S, Li L, Willard BB, Razzaque MS, He P (2021) Excessive inorganicphosphate burden perturbed intracellular signaling: quantitative proteomics and phosphoproteomicsanalyses. Front Nutr 8:765391. https://doi.org/10.3389/fnut.2021.765391

  53. Acquaviva J, Abdelhady HG, Razzaque MS (2022) Phosphate dysregulation and neurocognitive sequelae. In: Razzaque MS (ed) Phosphate metabolism, Advances in experimental medicine and biology 1362. Springer, Cham, pp 151–160

    Google Scholar 

Download references

Acknowledgement

I want to express my sincere gratitude to Dr. Nuraly Akimbekov (Al-Farabi Kazakh National University, Kazakhstan) for his help in drawing the illustrations. I also wish to thank Dr. Margo Wolfe for reading the manuscript and providing useful suggestions.

Author information

Authors and Affiliations

  1. Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA

    Mohammed S. Razzaque

Authors
  1. Mohammed S. Razzaque
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammed S. Razzaque .

Editor information

Editors and Affiliations

  1. Professor of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA

    Mohammed S. Razzaque

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Razzaque, M.S. (2022). Phosphate Metabolism: From Physiology to Toxicity. In: Razzaque, M.S. (eds) Phosphate Metabolism . Advances in Experimental Medicine and Biology, vol 1362. Springer, Cham. https://doi.org/10.1007/978-3-030-91623-7_1

Download citation

Publish with us

Policies and ethics

Search

Navigation