Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Bone and Mineral Metabolism
Published in: Journal of Bone and Mineral Metabolism 1/2020

01-01-2020 | Invited Review

How do we sense phosphate to regulate serum phosphate level?

Authors: Seiji Fukumoto, Yuichi Takashi, Maria K. Tsoumpra, Shun Sawatsubashi, Toshio Matsumoto

Published in: Journal of Bone and Mineral Metabolism | Issue 1/2020

Login to get access

Abstract

Abnormal phosphate levels result in several pathological conditions such as rickets/osteomalacia and ectopic calcification indicating that there must be a system that regulates phosphate level within a narrow range. FGF23 has been shown to be an essential hormone regulating serum phosphate level. FGF23 binds to Klotho-FGF receptor complex to reduce serum phosphate level. Several reports suggested that FGF receptor is involved in the regulation of FGF23 production. It has been also shown that high extracellular phosphate can activate several intracellular signaling pathways. However, it has been unclear whether and how phosphate regulates FGF23 production in vivo. Our recent results indicate that high extracellular phosphate directly activates FGF receptor 1 and the downstream intracellular signaling enhances FGF23 production. Thus, there is a negative feedback system for the regulation of serum phosphate level involving FGF receptor and FGF23. We propose that FGF receptor works at least as one of phosphate sensors in the maintenance of serum phosphate level.
Literature
1.
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 366:575–580PubMedCrossRef
2.
The ADHR Consortium (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348CrossRef
3.
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 98:6500–6505PubMedPubMedCentralCrossRef
4.
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 vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435PubMedCrossRef
5.
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 113:561–568PubMedPubMedCentralCrossRef
6.
Arai-Nunota N, Mizobuchi M, Ogata H, Yamazaki-Nakazawa A, Kumata C, Kondo F, Hosaka N, Koiwa F, Kinugasa E, Shibata T, Akizawa T (2014) Intravenous phosphate loading increases fibroblast growth factor 23 in uremic rats. PLoS One 9:e91096PubMedPubMedCentralCrossRef
7.
Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS (2006) Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 21:1187–1196PubMedCrossRef
8.
Ferrari SL, Bonjour JP, Rizzoli R (2005) Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90:1519–1524PubMedCrossRef
9.
Hori M, Kinoshita Y, Taguchi M, Fukumoto S (2016) Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells. J Bone Miner Metab 34:132–139PubMedCrossRef
10.
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 280:2543–2549PubMedCrossRef
11.
Bienaime F, Ambolet A, Aussilhou B, Brazier F, Fouchard M, Viau A, Barre P, Tissier AM, Correas JM, Paradis V, Terzi F, Friedlander G, Knebelmann B, Joly D, Prie D (2018) Hepatic production of fibroblast growth factor 23 in autosomal dominant polycystic kidney disease. J Clin Endocrinol Metab 103:2319–2328PubMedCrossRef
12.
Matsui I, Oka T, Kusunoki Y, Mori D, Hashimoto N, Matsumoto A, Shimada K, Yamaguchi S, Kubota K, Yonemoto S, Higo T, Sakaguchi Y, Takabatake Y, Hamano T, Isaka Y (2018) Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23. Kidney Int 94:60–71PubMedCrossRef
13.
14.
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 444:770–774PubMedCrossRef
15.
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 281:6120–6123PubMedCrossRef
16.
Gattineni J, Alphonse P, Zhang Q, Mathews N, Bates CM, Baum M (2014) Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol 306:F351–F358PubMedCrossRef
17.
Gattineni J, Twombley K, Goetz R, Mohammadi M, Baum M (2011) Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol 301:F371–F377PubMedPubMedCentralCrossRef
18.
19.
20.
Roberts MS, Burbelo PD, Egli-Spichtig D, Perwad F, Romero CJ, Ichikawa S, Farrow E, Econs MJ, Guthrie LC, Collins MT, Gafni RI (2018) Autoimmune hyperphosphatemic tumoral calcinosis in a patient with FGF23 autoantibodies. J Clin Invest 128:5368–5373PubMedPubMedCentralCrossRef
21.
Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2002) Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143:3179–3182PubMedCrossRef
22.
Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi 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 87:4957–4960PubMedCrossRef
23.
Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H (2003) Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348:1656–1663PubMedCrossRef
24.
Hang HC, Yu C, Ten Hagen KG, Tian E, Winans KA, Tabak LA, Bertozzi CR (2004) Small molecule inhibitors of mucin-type O-linked glycosylation from a uridine-based library. Chem Biol 11:337–345PubMedCrossRef
25.
Bennett EP, Mandel U, Clausen H, Gerken TA, Fritz TA, Tabak LA (2012) Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology 22:736–756PubMedCrossRef
26.
Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E (2004) Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36:579–581PubMedCrossRef
27.
Frishberg Y, Ito N, Rinat C, Yamazaki Y, Feinstein S, Urakawa I, Navon-Elkan P, Becher-Cohen R, Yamashita T, Araya K, Igarashi T, Fujita T, Fukumoto S (2007) Hyperostosis - hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res 22:235–242PubMedCrossRef
28.
Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H (2006) Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 281:18370–18377PubMedCrossRef
29.
30.
Michigami T, Kawai M, Yamazaki M, Ozono K (2018) Phosphate as a signaling molecule and its sensing mechanism. Physiol Rev 98:2317–2348PubMedCrossRef
31.
Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, Morii H, Giachelli CM (2000) Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 87:E10–E17PubMedCrossRef
32.
Naveh-Many T, Bell O, Silver J, Kilav R (2002) Cis and trans acting factors in the regulation of parathyroid hormone (PTH) mRNA stability by calcium and phosphate. FEBS Lett 529:60–64PubMedCrossRef
33.
Oshima Y, Akiyama T, Hikita A, Iwasawa M, Nagase Y, Nakamura M, Wakeyama H, Kawamura N, Ikeda T, Chung UI, Hennighausen L, Kawaguchi H, Nakamura K, Tanaka S (2008) Pivotal role of Bcl-2 family proteins in the regulation of chondrocyte apoptosis. J Biol Chem 283:26499–26508PubMedPubMedCentralCrossRef
34.
Uekawa A, Yamanaka H, Lieben L, Kimira Y, Uehara M, Yamamoto Y, Kato S, Ito K, Carmeliet G, Masuyama R (2018) Phosphate-dependent luminal ATP metabolism regulates transcellular calcium transport in intestinal epithelial cells. FASEB J 32:1903–1915PubMedCrossRef
35.
Beck GR Jr, Zerler B, Moran E (2000) Phosphate is a specific signal for induction of osteopontin gene expression. Proc Natl Acad Sci USA 97:8352–8357PubMedPubMedCentralCrossRef
36.
Kimata M, Michigami T, Tachikawa K, Okada T, Koshimizu T, Yamazaki M, Kogo M, Ozono K (2010) Signaling of extracellular inorganic phosphate up-regulates cyclin D1 expression in proliferating chondrocytes via the Na+/Pi cotransporter Pit-1 and Raf/MEK/ERK pathway. Bone 47:938–947PubMedCrossRef
37.
Nishino J, Yamazaki M, Kawai M, Tachikawa K, Yamamoto K, Miyagawa K, Kogo M, Ozono K, Michigami T (2017) Extracellular phosphate induces the expression of dentin matrix protein 1 through the FGF receptor in osteoblasts. J Cell Biochem 118:1151–1163PubMedCrossRef
38.
Beck GR Jr, Knecht N (2003) Osteopontin regulation by inorganic phosphate is ERK1/2-, protein kinase C-, and proteasome-dependent. J Biol Chem 278:41921–41929PubMedCrossRef
39.
Yamazaki M, Ozono K, Okada T, Tachikawa K, Kondou H, Ohata Y, Michigami T (2010) Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. J Cell Biochem 111:1210–1221PubMedCrossRef
40.
Takashi Y, Kosako H, Sawatsubashi S, Kinoshita Y, Ito N, Tsoumpra MK, Nangaku M, Abe M, Matsuhisa M, Kato S, Matsumoto T, Fukumoto S (2019) Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Proc Natl Acad Sci USA 116:11418–11427PubMedPubMedCentralCrossRef
41.
42.
Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM (2006) Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281:15694–15700PubMedCrossRef
43.
White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, McKeown C, Fitzpatrick D, Yu K, Ornitz DM, Econs MJ (2005) Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76:361–367PubMedCrossRef
44.
Kinoshita Y, Takashi Y, Ito N, Ikegawa S, Mano H, Ushiku T, Fukayama M, Nangaku M, Fukumoto S (2019) Ectopic expression of Klotho in fibroblast growth factor 23 (FGF23)-producing tumors that cause tumor-induced rickets/osteomalacia (TIO). Bone Rep 10:100192PubMedCrossRef
45.
Martin A, Liu S, David V, Li H, Karydis A, Feng JQ, Quarles LD (2011) Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25:2551–2562PubMedPubMedCentralCrossRef
46.
Wohrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M, Muller M, Kinzel B, Thuery A, Brueggen J, Hynes NE, Sellers WR, Hofmann F, Graus-Porta D (2011) FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone. J Bone Miner Res 26:2486–2497PubMedCrossRef
47.
Wohrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, Guagnano V, Sellers WR, Hofmann F, Kneissel M, Graus Porta D (2013) Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 28:899–911PubMedCrossRef
48.
Bon N, Frangi G, Sourice S, Guicheux J, Beck-Cormier S, Beck L (2018) Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2. Mol Metab 11:197–204PubMedPubMedCentralCrossRef
Metadata
Title
How do we sense phosphate to regulate serum phosphate level?
Authors
Seiji Fukumoto
Yuichi Takashi
Maria K. Tsoumpra
Shun Sawatsubashi
Toshio Matsumoto
Publication date
01-01-2020
Publisher
Springer Japan
Published in
Journal of Bone and Mineral Metabolism / Issue 1/2020
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-019-01066-0

Other articles of this Issue 1/2020

Journal of Bone and Mineral Metabolism 1/2020 Go to the issue

Original Article

Comparison of once-weekly teriparatide and alendronate against new osteoporotic vertebral fractures at week 12

Review Article

Updated concept of sarcopenia based on muscle–bone relationship

Original Article

A meta-analysis of bone morphogenetic protein-2 versus iliac crest bone graft for the posterolateral fusion of the lumbar spine

Letter to the Editor

Response to “Is grip strength an actual/significant predictor of areal bone mineral density by itself? Potential confounders and/or effect modifiers”

Original Article

Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis cases of the jaw

Original Article

Urolithiasis increases the risk of subsequent onset of osteoporosis
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits