Fibroblast growth factor 23 is pumping iron: C-terminal-fibroblast growth factor 23 cleaved peptide and its function in iron metabolism.

Journal

Current opinion in nephrology and hypertension

ISSN: 1473-6543

Titre abrégé: Curr Opin Nephrol Hypertens

Pays: England

ID NLM: 9303753

Informations de publication

Date de publication:
26 Apr 2024

Historique:

medline: 25 4 2024

pubmed: 25 4 2024

entrez: 25 4 2024

Statut: aheadofprint

Résumé

Iron deficiency regulates the production of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) but also its cleavage, to generate both intact (iFGF23) and C-terminal (Cter)-FGF23 peptides. Novel studies demonstrate that independently of the phosphaturic effects of iFGF23, Cter-FGF23 peptides play an important role in the regulation of systemic iron homeostasis. This review describes the complex interplay between iron metabolism and FGF23 biology. C-terminal (Cter) FGF23 peptides antagonize inflammation-induced hypoferremia to maintain a pool of bioavailable iron in the circulation. A key mechanism proposed is the down-regulation of the iron-regulating hormone hepcidin by Cter-FGF23. In this manuscript, we discuss how FGF23 is produced and cleaved in response to iron deficiency, and the principal functions of cleaved C-terminal FGF23 peptides. We also review possible implications anemia of chronic kidney disease (CKD).

Identifiants

DOI: 10.1097/MNH.0000000000000995 PMID: 38661434

pubmed: 38661434

doi: 10.1097/MNH.0000000000000995

pii: 00041552-990000000-00160

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Informations de copyright

Références

Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014; 123:615–624.

Stelle I, Kalea AZ, Pereira DIA. Iron deficiency anaemia: experiences and challenges. Proc Nutr Soc 2019; 78:19–26.

Krause A, Neitz S, Mägert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480:147–150.

Wang C-Y, Babitt JL. Liver iron sensing and body iron homeostasis. Blood 2019; 133:18–29.

Nemeth E, Ganz T. Hepcidin-ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci 2021; 22:6493.

David V, Martin A, Isakova T, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 2016; 89:135–146.

Munoz Mendoza J, Isakova T, Ricardo AC, et al. Fibroblast growth factor 23 and inflammation in CKD. Clin J Am Soc Nephrol 2012; 7:1155.

Bansal S, Friedrichs WE, Velagapudi C, et al. Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation. Nephrol Dial Transpl 2017; 32:960–968.

Durlacher-Betzer K, Hassan A, Levi R, et al. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int 2018; 94:315–325.

Glosse P, Fajol A, Hirche F, et al. A high-fat diet stimulates fibroblast growth factor 23 formation in mice through TNFα upregulation. Nutr Diabetes 2018; 8:1–6.

Egli-Spichtig D, Imenez Silva PH, Glaudemans B, et al. Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and nonrenal inflammation. Kidney Int 2019; 96:890–905.

Courbon G, Thomas JJ, Martinez-Calle M, et al. Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation. Blood 2023; 142:106–118.

Courbon G, Flammier S, Laroche N, et al. Tumor necrosis factor alpha overexpression induces mainly osteoclastogenesis at the vertebral site. Calcif Tissue Int 2017; 100:575–584.

Courbon G, Lamarque R, Gerbaix M, et al. Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model. Sci Rep 2018; 8:3492.

Courbon G, Rinaudo-Gaujous M, Blasco-Baque V, et al. Porphyromonas gingivalis experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat. Ann Rheum Dis 2019; 78:594–599.

Kitaura H, Marahleh A, Ohori F, et al. Osteocyte-related cytokines regulate osteoclast formation and bone resorption. Int J Mol Sci 2020; 21:5169.

Xu J, Yu L, Liu F, et al. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review. Front Immunol 2023; 14:1222129.

Katsumata S, Katsumata-Tsuboi R, Uehara M, et al. Severe iron deficiency decreases both bone formation and bone resorption in Rats1. J Nutr 2009; 139:238–243.

Messer JG, Cooney PT, Kipp DE. Iron chelator deferoxamine alters iron-regulatory genes and proteins and suppresses osteoblast phenotype in fetal rat calvaria cells. Bone 2010; 46:1408–1415.

Wright I, Blanco-Rojo R, Fernández MC, et al. Bone remodelling is reduced by recovery from iron-deficiency anaemia in premenopausal women. J Physiol Biochem 2013; 69:889–896.

Toxqui L, Pérez-Granados AM, Blanco-Rojo R, et al. Low iron status as a factor of increased bone resorption and effects of an iron and vitamin D-fortified skimmed milk on bone remodelling in young Spanish women. Eur J Nutr 2014; 53:441–448.

Noonan ML, Ni P, Solis E, et al. Osteocyte Egln1/Phd2 links oxygen sensing and biomineralization via FGF23. Bone Res 2023; 11:7.

Zhang Q, Doucet M, Tomlinson RE, et al. The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia. Bone Res 2016; 4:16011.

Latic N, Erben RG. FGF23 and vitamin D metabolism. JBMR Plus 2021; 5:e10558.

Portales-Castillo I, Simic P, FGF-23 PTH. Klotho and vitamin D as regulators of calcium and phosphorus: genetics, epigenetics and beyond. Front Endocrinol 2022; 13:992666.

Masuda Y, Ohta H, Morita Y, et al. Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice. Biol Pharm Bull 2015; 38:687–693.

Clinkenbeard EL, Hanudel MR, Stayrook KR, et al. Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. Haematologica 2017; 102:e427–e430.

Rabadi S, Udo I, Leaf DE, et al. Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol 2018; 314:F132–F139.

Courbon G, Francis C, Gerber C, et al. Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease. Bone Res 2021; 9:35.

Ishii S, Suzuki T, Wakahashi K, et al. FGF-23 from erythroblasts promotes hematopoietic progenitor mobilization. Blood 2021; 137:1457–1467.

Knab VM, Corbin B, Andrukhova O, et al. Acute parathyroid hormone injection increases C-terminal but not intact fibroblast growth factor 23 levels. Endocrinology 2017; 158:1130–1139.

Al Rifai O, Susan-Resiga D, Essalmani R, et al. In vivo analysis of the contribution of proprotein convertases to the processing of FGF23. Front Endocrinol 2021; 12:690681.

Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20:563–569.

Suzuki Y, Kuzina E, An SJ, et al. FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho. Proc Natl Acad Sci USA 2020; 117:31800–31807.

Agrawal A, Ni P, Agoro R, et al. Identification of a second Klotho interaction site in the C terminus of FGF23. Cell Rep 2021; 34:108665.

Chen L, Fu L, Sun J, et al. Structural basis for FGF hormone signalling. Nature 2023; 618:862–870.

Shimada T, Muto T, Urakawa I, et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002; 143:3179–3182.

Heijboer AC, Cavalier E. The Measurement and interpretation of fibroblast growth factor 23 (FGF23) Concentrations. Calcif Tissue Int 2023; 112:258–270.

Farrow EG, Yu X, Summers LJ, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci USA 2011; 108:E1146–1155.

Riminucci M, Collins MT, Fedarko NS, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003; 112:683–692.

Pereira RC, Juppner H, Azucena-Serrano CE, et al. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 2009; 45:1161–1168.

Han SS, Kim M, Kim H, et al. Nonlinear relationship between serum 25-hydroxyvitamin D and hemoglobin in Korean females: the Korean National Health and Nutrition Examination Survey 2010-2011. PLoS One 2013; 8:e72605.

Nakashima Y, Mima T, Yashiro M, et al. Expression and localization of fibroblast growth factor (FGF)23 and Klotho in the spleen: its physiological and functional implications. Growth Factors 2016; 34:196–202.

Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 2013; 28:1793–1803.

Moe SM, Chertow GM, Parfrey PS, et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation 2015; 132:27–39.

Maruyama N, Otsuki T, Yoshida Y, et al. Ferric citrate decreases fibroblast growth factor 23 and improves erythropoietin responsiveness in hemodialysis patients. Am J Nephrol 2018; 47:406–414.

Francis C, Courbon G, Gerber C, et al. Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease. Kidney Int 2019; 96:1346–1358.

Block GA, Chertow GM, Cooper K, et al. Fibroblast growth factor 23 as a risk factor for cardiovascular events and mortality in patients in the EVOLVE trial. Hemodial Int Int Symp Home Hemodial 2021; 25:78–85.

Agoro R, Montagna A, Goetz R, et al. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. FASEB J 2018; 32:3752–3764.

Park MY, Le Henaff C, Sitara D. Administration of α-Klotho does not rescue renal anemia in mice. Front Pediatr 2022; 10:924915.

Egli-Spichtig D, Hamid AK, Arroyo EMP, et al. Intact FGF23 predicts serum phosphate improvement after combined nicotinamide and phosphate binder treatment in hemodialysis patients. Clin Kidney J 2023; 16:1622–1633.

Chu C, Elitok S, Zeng S, et al. C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival. BMC Nephrol 2021; 22:125.

Thomas E, Klomhaus AM, Laster ML, et al. Associations between anemia and FGF23 in the CKiD study. Pediatr Nephrol Berl Ger 2023; 39:837–847.

Courbon G, David V. Lipocalin-2: a novel link between the injured kidney and the bone. Curr Opin Nephrol Hypertens 2022; 31:312–319.

Martin A, David V. Transcriptomics: a solution for renal osteodystrophy? Curr Osteoporos Rep 2020; 18:254–261.

Zittermann A, Jungvogel A, Prokop S, et al. Vitamin D deficiency is an independent predictor of anemia in end-stage heart failure. Clin Res Cardiol 2011; 100:781–788.

Ernst JB, Becker T, Kuhn J, et al. Independent association of circulating vitamin D metabolites with anemia risk in patients scheduled for cardiac surgery. PLoS One 2015; 10:e0124751.

Azizi-Soleiman F, Vafa M, Abiri B, et al. Effects of iron on vitamin d metabolism: a systematic review. Int J Prev Med 2016; 7:126.

Gurina TS, Mohiuddin SS. Biochemistry, protein catabolism. StatPearls. Treasure Island (FL): StatPearls Publishing 2024. http://www.ncbi.nlm.nih.gov/books/NBK556047/ (accessed 8 April 2024).

Christov M, Waikar S, Pereira R, et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int 2013; 84:776–785.

Sharma S, Katz R, Ginsberg C, et al. Renal clearance of fibroblast growth factor-23 (FGF23) and its fragments in humans. J Bone Miner Res 2022; 37:1170–1178.

Sharma S, Ix JH. Kidney clearance of fibroblast growth factor-23 in humans. Curr Opin Nephrol Hypertens 2023; 32:330–334.

Becker KL, Nylén ES, White JC, et al. Clinical review 167: procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004; 89:1512–1525.

Yamakoshi Y. Dentin sialophophoprotein (DSPP) and dentin. J Oral Biosci 2008; 50:33–44.

Yeo GSH, Chao DHM, Siegert A-M, et al. The melanocortin pathway and energy homeostasis: from discovery to obesity therapy. Mol Metab 2021; 48:101206.

Pellegrini H, Sharpe EH, Liu G, et al. Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction. J Biol Chem 2023; 299:105158.

Coe LM, Madathil SV, Casu C, et al. FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J Biol Chem 2014; 289:9795–9810.

Mehta R, Cai X, Hodakowski A, et al. Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study. Clin J Am Soc Nephrol 2017; 12:1795–1803.

Dussold C, Gerber C, White S, et al. DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease. Bone Res 2019; 7:12.