Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in
                    Beta-Thalassemia

Dimitrios Stefanopoulos; Narjes Nasiri-Ansari; Ismene Dontas; Andromachi Vryonidou; Antonis Galanos; Loukia Psaridi; Ioannis G. Fatouros; George Mastorakos; Athanasios G. Papavassiliou; Eva Kassi; Symeon Tournis

doi:10.1055/a-1104-5326

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2020; 52(03): 194-201
DOI: 10.1055/a-1104-5326

Endocrine Research

Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in Beta-Thalassemia

Authors

Dimitrios Stefanopoulos

¹Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, National and Kapodistrian University of Athens, Athens, Greece
Narjes Nasiri-Ansari

²Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
Ismene Dontas

¹Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, National and Kapodistrian University of Athens, Athens, Greece
Andromachi Vryonidou

³Department of Endocrinology, Diabetes, & Metabolism, General Hospital “Korgialenio-Benakio”, Athens, Greece
Antonis Galanos

¹Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, National and Kapodistrian University of Athens, Athens, Greece
Loukia Psaridi

⁴Department of Biochemistry, Hellenic Red Cross Hospital, Athens, Greece
Ioannis G. Fatouros

⁵Department of Physical Education & Sport Science, University of Thessaly, Karies, Greece
George Mastorakos

⁶Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
Athanasios G. Papavassiliou

²Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
Eva Kassi‡

²Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece

⁷First Department of Internal Medicine, Laikon Hospital- National and Kapodistrian University of Athens, Athens, Greece
Symeon Tournis‡

¹Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, National and Kapodistrian University of Athens, Athens, Greece

Abstract

Derangements in phosphate and calcium homeostasis are common in patients with beta-thalassemia. Fibroblast growth factor 23 (FGF23) is among the main hormones regulating phosphate levels, while several studies underline an interplay between iron (Fe) and FGF23. Herein, we investigated, for the first time, the serum intact molecule (iFGF23) and the carboxyl-terminal fragment (C-FGF23) and Klotho levels simultaneously in patients with beta-thalassemia major receiving iron chelation regimens in comparison to healthy control subjects. We also correlated them with the body iron burden. The observational case-control study included 81 subjects (40 thalassemic patients and 41 healthy controls). Serum iFGF23, C-FGF23 and Κlotho were measured by ELISA. Parathormone, 25-hydroxycholecalciferol, calcium, and phosphorus were measured in blood and/or urine. The degree of hemosiderosis was evaluated by assessing the serum ferritin levels and performing T2* MRI measurements. Serum C-FGF23 levels were significantly lower in patients compared to control subjects (p=0.04), while iFGF23 and Klotho levels did not differ. Serum C-FGF23 levels were negatively correlated with ferritin (r=–0,421, p=0.018), whereas there were no significant correlations of each of the three factors with the iron chelation therapy. Decreased serum C-FGF23 levels were found in βTh patients which may be attributed to inhibition of proteolytic cleavage of iFGF23. Further studies in a greater number of patients will shed more light on the disturbances of the iFGF23, Klotho and C-FGF23 in thalassemia and their possible role in bone disease of such patients.

Key words

FGF23 - C-terminal FGF23 - phosphorus - beta-thalassemia - ferritin - chelation

Full Text

References

References
1 Penido MG, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol 2012; 27: 2039-2048
2 Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 2010; 61: 91-104
3 Hu MC, Shiizaki K, Kuro-o M. et al. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 2013; 75: 503-533
4 Ramon I, Kleynen P, Body JJ. et al. Fibroblast growth factor 23 and its role in phosphate homeostasis. Europ J Endocrinol 2010; 162: 1-10
5 Gattineni J, Bates C, Twombley K. et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297: 282-291
6 Cappellini MD, Cohen A, Porter J. et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). 3rd edition, Nicosia (CY): Thalassaemia International Federation; 2014
7 Stefanopoulos D, Papaioannou NA, Papavassiliou AG. et al. A contemporary therapeutic approach to bone disease in beta-thalassemia - a review. J Frailty Sarcopenia Falls 2018; 3: 13-25
8 Baldini M, Forti S, Marcon A, Ulivieri FM. et al. Endocrine and bone disease in appropriately treated adult patients with beta-thalassemia major. Ann Hematol 2010; 89: 1207-1213
9 Vogiatzi MG, Macklin EA, Fung EB. et al. Bone disease in thalassemia: A frequent and still unresolved problem. J Bone Miner Res 2009; 24: 543-557
10 Vogiatzi MG, Macklin EA, Fung EB. et al. Prevalence of fractures among the Thalassemia syndromes in North America. Bone 2006; 38: 571-575
11 Sutipornpalangkul W, Janechetsadatham Y, Siritanaratkul N. et al Prevalence of fractures among Thais with thalassaemia syndromes. Singapore Med J 2010; 51: 817-821
12 Toumba M, Skordis N. Osteoporosis syndrome in thalassaemia major: An overview. J Osteoporos 2010; 53673: 1-7
13 Schouten BJ, Doogue MP, Soule SG. et al. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem 2009; 46: 167-169
14 Schouten BJ, Hunt PJ, Livesey JH. et al. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: A prospective study. J Clin Endocrinol Metab 2009; 94: 2332-2337
15 Shimizu Y, Tada Y, Yamauchi M. et al. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: Another form of FGF23-related hypophosphatemia. Bone 2009; 45: 814-816
16 Takeda Y, Komaba H, Goto S. et al. Effect of intravenous saccharated ferric oxide on serum FGF23 and mineral metabolism in hemodialysis patients. Am J Nephrol 2011; 33: 421-426
17 Hryszko T, Rydzewska-Rosolowska A, Brzoski S. et al. Low molecular weight iron dextran increases fibroblast growth factor-23 concentration together with parathyroid hormone decrease in hemodialyzed patients. Ther Apher Dial 2012; 16: 146-151
18 Braithwaite V, Prentice AM, Doherty C. et al. FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: A supplementation study. Int J Pediatr Endocrinol. 2012 27.
19 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
20 Prats M, Font R, Garcia C. et al. Effect of ferric carboxymaltose on serum phosphate and C-terminal FGF23 levels in non-dialysis chronic kidney disease patients: Post-hoc analysis of a prospective study. BMC Nephrol 2013; 14: 167
21 Hardy S, Vandemergel X. Intravenous iron administration and hypophosphatemia in clinical practice. Int J Rheumatol 2015; 2015: 1-6
22 Schaefer B, Würtinger P, Finkenstedt A. et al. Choice of high-dose intravenous iron preparation determines hypophosphatemia risk. PLoS One 2016; 11: e0167146
23 Elsenga MF, van Londen M, Leaf DE. et al. C-Terminal fibroblast growth factor 23, iron deficiency, and mortality in renal transplant recipients. J Am Soc Nephrol 2017; 28: 3639-3646
24 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
25 Ferro E, Visalli G, Curro M. et al. HIF1α and Glut1 receptor in transfused and untransfused thalassemic patients. Br J Haematol 2016; 174: 824-826
26 Tangngam H, Mahachoklertwattana P, Poomthavorn P. et al. Under-recognized hypoparathyroidism in thalassemia. J Clin Res Pediatr Endocrinol 2018; 10: 324-330
27 Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): Indications and interpretation. Ann Clin Biochem 1998; 35: 201-206
28 Walton RJ, Bijvoet OL. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975; 2: 309-310
29 Wood JC, Enriquez C, Ghugre N. et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood 2005; 106: 1460-1465
30 David V, Dai B, Martin A. et al. Calcium regulates FGF-23 expression in bone. Endocrinology 2013; 154: 4469-4482
31 Ho PJ, Tay L, Lindeman R. et al. Australian Guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle-cell disease and other congenital anaemias. Intern Med J 2011; 41: 516-524
32 Tsuji K, Maeda T, Kawane T. et al. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. J Bone Miner Res 2010; 25: 1711-1723
33 Muras-Szwedziak K, Nowicki M. Associations between intravenous iron, inflammation and FGF23 in non-dialysis patients with chronic kidney disease stages 3-5. Kidney Blood Pres Res 2018; 43: 143-151
34 Huang Y, Lei Y, Liu R. et al. Imbalance of erythropoiesis and iron metabolism in patients with thalassemia. Int J Med Sci 2019; 16: 302-310
35 van Vuren AJ, CAJM Gaillard, Eisenga MF. et al. The EPO-FGF23 signaling pathway in erythroid progenitor cells: opening a new area of research. Front Physiol 2019; 10: 304
36 Baldan A, Giusti A, Bosi C. et al. Klotho, a new marker for osteoporosis and muscle strength in β-thalassemia major. Blood Cells Mol Dis 2015; 55: 396-401
37 Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 2014; 6: 748-773
38 Italian Working Group on Endocrine Complications in Non-Endocrine Diseases Multicentre study on prevalence of endocrine complications in thalassaemia major. Clin Endocrinol (Oxf) 1995; 42: 581-586
39 Karim MF, Ismail M, Hasan AM. et al. Hematological and biochemical status of Beta-thalassemia major patients in Bangladesh: A comparative analysis. Int J Hematol Oncol Stem Cell Res 2016; 10: 7-12
40 Moukhadder HM, Halawi R, Cappellini MD. et al. Hepatocellular carcinoma as an emerging morbidity in the thalassemia syndromes: A comprehensive review. Cancer 2017; 123: 751-758
41 Goyal M, Abrol P, Lal H. Parathyroid and calcium status in patients with thalassemia. Indian J Clin Biochem 2010; 25: 385-387
42 Sultan S, Irfan SM, Ahmed SI. Biochemical markers of bone turnover in patients with β-thalassemia major: A single center study from Southern Pakistan. Adv Hematol 2016; 2016: 5437609
43 Pratico G, Di Gregorio F, Caltabiano L. et al. Calcium phosphate metabolism in thalassemia. Pediatr Med Chir 1998; 20: 265-268
44 Machachoklertwattana P, Pootrakul P, Chuansumrit A. et al. Association between bone mineral density and erythropoiesis in Thai children and adolescents with thalassemia syndromes. J Bone Miner Metab 2006; 24: 146-152
45 Angelopoulos NG, Goula A, Rombopoulos G. et al. Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. J Bone Miner Metab 2006; 24: 138-145
46 Vogiatzi MG, Macklin EA, Trachtenberg FL. et al. Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America. Br J Haematol 2009; 146: 546-556
47 Napoli N, Carmina E, Bucchieri S. et al. Low serum levels of 25-hydroxy vitamin D in adults affected by thalassemia major or intermedia. Bone 2006; 38: 888-892
48 Wong P, Fuller PJ, Gillespie MT. et al. Thalassemia bone disease: the association between nephrolithiasis, bone mineral density and fractures. Osteoporos Int 2013; 24: 1965-1971
49 Quinn CT, Johnson VL, Kim HY. et al. Renal dysfunction in patients with thalassaemia. Br J Haematol 2011; 153: 111-117
50 Wong P, Polkinghorne K, Kerr PG. et al. Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria. Bone 2016; 85: 55-58
51 Mula-Abed WA, Al-Hashmi HS, Al-Muslahi MN. Indicators of renal glomerural and tubular functions in patients with beta-thalassemia major. A cross sectional study at the Royal Hospital, Oman. Sultan Qaboos Univ Med J 2011; 11: 69-76
52 Aldudak B, Karabay Bayazit A, Noyan A. et al. Renal function in pediatric patients with beta-thalassemia major. Pediatr Nephrol 2000; 15: 109-112

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