The Journal of Physiological Sciences

, Volume 68, Issue 3, pp 221–232 | Cite as

Intestinal calcium transport and its regulation in thalassemia: interaction between calcium and iron metabolism

  • Kornkamon Lertsuwan
  • Kannikar Wongdee
  • Jarinthorn Teerapornpuntakit
  • Narattaphol Charoenphandhu


Osteoporosis and derangement of calcium homeostasis are common complications of thalassemia. Despite being an important process for bone and calcium metabolism, little is known about intestinal calcium transport in thalassemia. Recent reports of decreases in both intestinal calcium transport and bone mineral density in thalassemic patients and animal models suggested that defective calcium absorption might be a cause of thalassemic bone disorder. Herein, the possible mechanisms associated with intestinal calcium malabsorption in thalassemia are discussed. This includes alterations in the calcium transporters and hormonal controls of the transcellular and paracellular intestinal transport systems in thalassemia. In addition, the effects of iron overload on intestinal calcium absorption, and the reciprocal interaction between iron and calcium transport in thalassemia are elaborated. Understanding the mechanisms underlining calcium malabsorption in thalassemia would lead to development of therapeutic agents and mineral supplements that restore calcium absorption as well as prevent osteoporosis in thalassemic patients.


Calcium transport Iron transport Osteoporosis Thalassemia Vitamin D 



The authors would like to thank Prof. Nateetip Krishnamra for critical comments and proofreading of the manuscript.


N. Charoenphandhu has been supported by the Thailand Research Fund (TRF) through TRF Senior Research Scholar Grant (RTA6080007). K. Wongdee has been supported by TRF International Research Network (IRN) Grant (IRN60W0001).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Christakos S, Dhawan P, Porta A, Mady LJ, Seth T (2011) Vitamin D and intestinal calcium absorption. Mol Cell Endocrinol 347:25–29PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Fleet JC, Eksir F, Hance KW, Wood RJ (2002) Vitamin D-inducible calcium transport and gene expression in three Caco-2 cell lines. Am J Physiol Gastrointest Liver Physiol 283:G618–G625PubMedCrossRefGoogle Scholar
  3. 3.
    Jaeger P, Jones W, Clemens TL, Hayslett JP (1986) Evidence that calcitonin stimulates 1,25-dihydroxyvitamin D production and intestinal absorption of calcium in vivo. J Clin Invest 78:456–461PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Nemere I, Larsson D (2002) Does PTH have a direct effect on intestine? J Cell Biochem 86:29–34PubMedCrossRefGoogle Scholar
  5. 5.
    Wongdee K, Charoenphandhu N (2015) Vitamin D-enhanced duodenal calcium transport. Vitam Horm 98:407–440PubMedCrossRefGoogle Scholar
  6. 6.
    Kelly N (2012) Thalassemia. Pediatr Rev 33:434–435PubMedCrossRefGoogle Scholar
  7. 7.
    Muncie HL, Campbell J (2009) Alpha and beta thalassemia. Am Fam Physician 80:339–344PubMedGoogle Scholar
  8. 8.
    Haidar R, Musallam KM, Taher AT (2011) Bone disease and skeletal complications in patients with β thalassemia major. Bone 48:425–432PubMedCrossRefGoogle Scholar
  9. 9.
    Nienhuis AW, Nathan DG (2012) Pathophysiology and clinical manifestations of the β-thalassemias. Cold Spring Harb Perspect Med 2:a011726PubMedPubMedCentralGoogle Scholar
  10. 10.
    Liakakos D, Vlachos P, Anoussakis C, Constantinides C, Tsakalosos I (1976) Calcium metabolism in children suffering from homozygous β-thalassaemia after oral administration of 47Ca. Nuklearmedizin 15:77–79PubMedCrossRefGoogle Scholar
  11. 11.
    Charoenphandhu N, Kraidith K, Teerapornpuntakit J, Thongchote K, Khuituan P, Svasti S, Krishnamra N (2013) 1,25-Dihydroxyvitamin D3-induced intestinal calcium transport is impaired in β-globin knockout thalassemic mice. Cell Biochem Funct 31:685–691PubMedCrossRefGoogle Scholar
  12. 12.
    Kraidith K, Svasti S, Teerapornpuntakit J, Vadolas J, Chaimana R, Lapmanee S, Suntornsaratoon P, Krishnamra N, Fucharoen S, Charoenphandhu N (2016) Hepcidin and 1,25(OH)2D3 effectively restore Ca2+ transport in β-thalassemic mice: reciprocal phenomenon of Fe2+ and Ca2+ absorption. Am J Physiol Endocrinol Metab 311:E214–E223PubMedCrossRefGoogle Scholar
  13. 13.
    Carmeliet G, Dermauw V, Bouillon R (2015) Vitamin D signaling in calcium and bone homeostasis: a delicate balance. Best Pract Res Clin Endocrinol Metab 29:621–631PubMedCrossRefGoogle Scholar
  14. 14.
    Hagino H (2015) Vitamin D3 analogs for the treatment of osteoporosis. Can J Physiol Pharmacol 93:327–332PubMedCrossRefGoogle Scholar
  15. 15.
    Kellett GL (2011) Alternative perspective on intestinal calcium absorption: proposed complementary actions of Cav1.3 and TRPV6. Nutr Rev 69:347–370PubMedCrossRefGoogle Scholar
  16. 16.
    Schröder B, Schlumbohm C, Kaune R, Breves G (1996) Role of calbindin-D9k in buffering cytosolic free Ca2+ ions in pig duodenal enterocytes. J Physiol 492:715–722PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Timmermans JAH, Bindels RJM, Van Os CH (1995) Stimulation of plasma membrane Ca2+ pump by Calbindin-D28k and calmodulin is additive in EGTA-free solutions. J Nutr 125:1981S–1986SPubMedCrossRefGoogle Scholar
  18. 18.
    Walters JR (1989) Calbindin-D9k stimulates the calcium pump in rat enterocyte basolateral membranes. Am J Physiol 256:G124–G128PubMedGoogle Scholar
  19. 19.
    Charoenphandhu N, Krishnamra N (2007) Prolactin is an important regulator of intestinal calcium transport. Can J Physiol Pharmacol 85:569–581PubMedCrossRefGoogle Scholar
  20. 20.
    Charoenphandhu N, Wongdee K, Krishnamra N (2010) Is prolactin the cardinal calciotropic maternal hormone? Trends Endocrinol Metab 21:395–401PubMedCrossRefGoogle Scholar
  21. 21.
    Karbach U (1992) Paracellular calcium transport across the small intestine. J Nutr 122:672–677PubMedCrossRefGoogle Scholar
  22. 22.
    Tanrattana C, Charoenphandhu N, Limlomwongse L, Krishnamra N (2004) Prolactin directly stimulated the solvent drag-induced calcium transport in the duodenum of female rats. Biochim Biophys Acta 1665:81–91PubMedCrossRefGoogle Scholar
  23. 23.
    Fujita H, Sugimoto K, Inatomi S, Maeda T, Osanai M, Uchiyama Y, Yamamoto Y, Wada T, Kojima T, Yokozaki H, Yamashita T, Kato S, Sawada N, Chiba H (2008) Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Mol Biol Cell 19:1912–1921PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Karim MF, Ismail M, Hasan AM, Shekhar HU (2016) Hematological and biochemical status of Beta-thalassemia major patients in Bangladesh: a comparative analysis. Int J Hematol Oncol Stem Cell Res 10:7–12PubMedPubMedCentralGoogle Scholar
  25. 25.
    Kopic S, Geibel JP (2013) Gastric acid, calcium absorption, and their impact on bone health. Physiol Rev 93:189–268PubMedCrossRefGoogle Scholar
  26. 26.
    Peacock M (2010) Calcium metabolism in health and disease. Clin J Am Soc Nephrol 5:S23–S30PubMedCrossRefGoogle Scholar
  27. 27.
    Picotto G, Massheimer V, Boland R (1997) Parathyroid hormone stimulates calcium influx and the cAMP messenger system in rat enterocytes. Am J Physiol 273:C1349–C1353PubMedCrossRefGoogle Scholar
  28. 28.
    Nemere I, Szego CM (1981) Early actions of parathyroid hormone and 1,25-dihydroxycholecalciferol on isolated epithelial cells from rat intestine: I. Limited lysosomal enzyme release and calcium uptake. Endocrinology 108:1450–1462PubMedCrossRefGoogle Scholar
  29. 29.
    Chen RA, Goodman WG (2004) Role of the calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol 286:F1005–F1011PubMedCrossRefGoogle Scholar
  30. 30.
    Cianferotti L, Gomes AR, Fabbri S, Tanini A, Brandi ML (2015) The calcium-sensing receptor in bone metabolism: from bench to bedside and back. Osteoporos Int 26:2055–2071PubMedCrossRefGoogle Scholar
  31. 31.
    Khuituan P, Teerapornpuntakit J, Wongdee K, Suntornsaratoon P, Konthapakdee N, Sangsaksri J, Sripong C, Krishnamra N, Charoenphandhu N (2012) Fibroblast growth factor-23 abolishes 1,25-dihydroxyvitamin D3-enhanced duodenal calcium transport in male mice. Am J Physiol Endocrinol Metab 302:E903–E913PubMedCrossRefGoogle Scholar
  32. 32.
    Khuituan P, Wongdee K, Jantarajit W, Suntornsaratoon P, Krishnamra N, Charoenphandhu N (2013) Fibroblast growth factor-23 negates 1,25(OH)2D3-induced intestinal calcium transport by reducing the transcellular and paracellular calcium fluxes. Arch Biochem Biophys 536:46–52PubMedCrossRefGoogle Scholar
  33. 33.
    Yoshiko Y, Wang H, Minamizaki T, Ijuin C, Yamamoto R, Suemune S, Kozai K, Tanne K, Aubin JE, Maeda N (2007) Mineralized tissue cells are a principal source of FGF23. Bone 40:1565–1573PubMedCrossRefGoogle Scholar
  34. 34.
    Jüppner H (2011) Phosphate and FGF-23. Kidney Int 79121:S24–S27PubMedCrossRefGoogle Scholar
  35. 35.
    Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK (2005) 1α,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 289:G1036–G1042PubMedCrossRefGoogle Scholar
  36. 36.
    Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, Ono K, Kakitani M, Tomizuka K, Fujita T, Fukumoto S, Yamashita T (2005) Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 289:F1088–F1095PubMedCrossRefGoogle Scholar
  37. 37.
    Skordis N, Toumba M (2011) Bone disease in thalassaemia major: recent advances in pathogenesis and clinical aspects. Pediatr Endocrinol Rev 8:300–306PubMedGoogle Scholar
  38. 38.
    Wong P, Fuller PJ, Gillespie MT, Milat F (2016) Bone disease in thalassemia: a molecular and clinical overview. Endocr Rev 37:320–346PubMedCrossRefGoogle Scholar
  39. 39.
    Soliman AT, El Banna N, Abdel Fattah M, ElZalabani MM, Ansari BM (1998) Bone mineral density in prepubertal children with & #x03B2;-thalassemia: correlation with growth and hormonal data. Metabolism 47:541–548PubMedCrossRefGoogle Scholar
  40. 40.
    Benigno V, Bertelloni S, Baroncelli GI, Bertacca L, Di Peri S, Cuccia L, Borsellino Z, Maggio MC (2003) Effects of thalassemia major on bone mineral density in late adolescence. J Pediatr Endocrinol Metab 16:337–342PubMedGoogle Scholar
  41. 41.
    Mahachoklertwattana P, Chuansumrit A, Sirisriro R, Choubtum L, Sriphrapradang A, Rajatanavin R (2003) Bone mineral density, biochemical and hormonal profiles in suboptimally treated children and adolescents with β-thalassaemia disease. Clin Endocrinol (Oxf) 58:273–279CrossRefGoogle Scholar
  42. 42.
    Merchant R, Udani A, Puri V, D’Cruz V, Patkar D, Karkera A (2010) Evaluation of osteopathy in thalassemia by bone mineral densitometry and biochemical indices. Indian J Pediatr 77:987–991PubMedCrossRefGoogle Scholar
  43. 43.
    Soliman A, Adel A, Bedair E, Wagdy M (2008) An adolescent boy with thalassemia major presenting with bone pain, numbness, tetanic contractions and growth and pubertal delay: panhypopituitarism and combined vitamin D and parathyroid defects. Pediatr Endocrinol Rev 6:155–157PubMedGoogle Scholar
  44. 44.
    Vogiatzi MG, Macklin EA, Fung EB, Vichinsky E, Olivieri N, Kwiatkowski J, Cohen A, Neufeld E, Giardina PJ (2006) Prevalence of fractures among the Thalassemia syndromes in North America. Bone 38:571–575PubMedCrossRefGoogle Scholar
  45. 45.
    Vogiatzi MG, Macklin EA, Fung EB, Cheung AM, Vichinsky E, Olivieri N, Kirby M, Kwiatkowski JL, Cunningham M, Holm IA, Lane J, Schneider R, Fleisher M, Grady RW, Peterson CC, Giardina PJ, Thalassemia Clinical Research N (2009) Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Miner Res 24:543–557PubMedCrossRefGoogle Scholar
  46. 46.
    Thongchote K, Svasti S, Sa-ardrit M, Krishnamra N, Fucharoen S, Charoenphandhu N (2011) Impaired bone formation and osteopenia in heterozygous βIVSII−654 knockin thalassemic mice. Histochem Cell Biol 136:47–56PubMedCrossRefGoogle Scholar
  47. 47.
    Thongchote K, Svasti S, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N (2014) Running exercise alleviates trabecular bone loss and osteopenia in hemizygous β-globin knockout thalassemic mice. Am J Physiol Endocrinol Metab 306:E1406–E1417PubMedCrossRefGoogle Scholar
  48. 48.
    Thongchote K, Svasti S, Teerapornpuntakit J, Suntornsaratoon P, Krishnamra N, Charoenphandhu N (2015) Bone microstructural defects and osteopenia in hemizygous βIVSII−654 knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function. Am J Physiol Endocrinol Metab 309:E936–E948PubMedCrossRefGoogle Scholar
  49. 49.
    Morabito N, Russo GT, Gaudio A, Lasco A, Catalano A, Morini E, Franchina F, Maisano D, La Rosa M, Plota M, Crifo A, Meo A, Frisina N (2007) The “lively” cytokines network in β-thalassemia major-related osteoporosis. Bone 40:1588–1594PubMedCrossRefGoogle Scholar
  50. 50.
    Oztürk O, Yaylim I, Aydin M, Yilmaz H, Agaçhan B, Demiralp E, Isbir T (2001) Increased plasma levels of interleukin-6 and interleukin-8 in β-thalassaemia major. Haematologia (Budap) 31:237–244CrossRefGoogle Scholar
  51. 51.
    Wanachiwanawin W, Wiener E, Siripanyaphinyo U, Chinprasertsuk S, Mawas F, Fucharoen S, Wickramasinghe SN, Pootrakul P, Visudhiphan S (1999) Serum levels of tumor necrosis factor-α, interleukin-1, and interferon-γ in β°-thalassemia/HbE and their clinical significance. J Interferon Cytokine Res 19:105–111PubMedCrossRefGoogle Scholar
  52. 52.
    Dundar U, Kupesiz A, Ozdem S, Gilgil E, Tuncer T, Yesilipek A, Gultekin M (2007) Bone metabolism and mineral density in patients with beta-thalassemia major. Saudi Med J 28:1425–1429PubMedGoogle Scholar
  53. 53.
    Saki N, Abroun S, Salari F, Rahim F, Shahjahani M, Javad MA (2015) Molecular aspects of bone resorption in β-thalassemia major. Cell J 17:193–200PubMedPubMedCentralGoogle Scholar
  54. 54.
    Voskaridou E, Christoulas D, Xirakia C, Varvagiannis K, Boutsikas G, Bilalis A, Kastritis E, Papatheodorou A, Terpos E (2009) Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration. Haematologica 94:725–728PubMedGoogle Scholar
  55. 55.
    Voskaridou E, Christoulas D, Plata E, Bratengeier C, Anastasilakis AD, Komninaka V, Kaliontzi D, Gkotzamanidou M, Polyzos SA, Dimopoulou M, Terpos E (2012) High circulating sclerostin is present in patients with thalassemia-associated osteoporosis and correlates with bone mineral density. Horm Metab Res 44:909–913PubMedCrossRefGoogle Scholar
  56. 56.
    Aleem A, Al-Momen AK, Al-Harakati MS, Hassan A, Al-Fawaz I (2000) Hypocalcemia due to hypoparathyroidism in β-thalassemia major patients. Ann Saudi Med 20:364–366PubMedCrossRefGoogle Scholar
  57. 57.
    Goyal M, Abrol P, Lal H (2010) Parathyroid and calcium status in patients with thalassemia. Indian J Clin Biochem 25:385–387PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Charoenphandhu N, Kraidith K, Lertsuwan K, Sripong C, Suntornsaratoon P, Svasti S, Krishnamra N, Wongdee K (2017) Na+/H+ exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous β-globin knockout thalassemic mice. Mol Cell Biochem 427:201–208PubMedCrossRefGoogle Scholar
  59. 59.
    Sharon P, Karmeli F, Rachmilewitz D (1982) Decreased jejunal (Na + K)-ATPase activity in pernicious anemia. Dig Dis Sci 27:1143PubMedCrossRefGoogle Scholar
  60. 60.
    Callahan LS, Thibert KA, Wobken JD, Georgieff MK (2013) Early-life iron deficiency anemia alters the development and long-term expression of parvalbumin and perineuronal nets in the rat hippocampus. Dev Neurosci 35:427–436PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Matak P, Zumerle S, Mastrogiannaki M, El Balkhi S, Delga S, Mathieu JR, Canonne-Hergaux F, Poupon J, Sharp PA, Vaulont S, Peyssonnaux C (2013) Copper deficiency leads to anemia, duodenal hypoxia, upregulation of HIF-2alpha and altered expression of iron absorption genes in mice. PLoS ONE 8:e59538PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Michalitsi V, Dafopoulos K, Gourounti K, Messini C, Ioannou M, Christodoulaki C, Panagopoulos P, Messinis I (2015) Hypoxia-inducible factor-1α (HIF-1α) expression in placentae of women with iron deficiency anemia and β-thalassemia trait. J Matern Fetal Neonatal Med 28:470–474PubMedCrossRefGoogle Scholar
  63. 63.
    Ziello JE, Jovin IS, Huang Y (2007) Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med 80:51–60PubMedPubMedCentralGoogle Scholar
  64. 64.
    Wu J, Sun X, Wu Q, Li H, Li L, Feng J, Zhang S, Xu L, Li K, Li X, Wang X, Chen H (2016) Disrupted intestinal structure in a rat model of intermittent hypoxia. Mol Med Rep 13:4407–4413PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang J, Wang P, He W, Wang F (2016) Changes in expression of Slingshot protein in hypoxic human intestinal epithelial cell and its relation with barrier function of the cells. Zhonghua Shao Shang Za Zhi 32:249–253PubMedGoogle Scholar
  66. 66.
    Okano T, Tsugawa N, Morishita A, Kato S (2004) Regulation of gene expression of epithelial calcium channels in intestine and kidney of mice by 1α,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 89–90:335–338PubMedCrossRefGoogle Scholar
  67. 67.
    Ghijsen WE, De Jong MD, Van Os CH (1983) Kinetic properties of Na+/Ca2+ exchange in basolateral plasma membranes of rat small intestine. Biochim Biophys Acta 730:85–94PubMedCrossRefGoogle Scholar
  68. 68.
    Centeno V, Picotto G, Perez A, Alisio A, Tolosa de Talamoni N (2011) Intestinal Na+/Ca2+ exchanger protein and gene expression are regulated by 1,25(OH)2D3 in vitamin D-deficient chicks. Arch Biochem Biophys 509:191–196PubMedCrossRefGoogle Scholar
  69. 69.
    Aloia JF, Ostuni JA, Yeh JK, Zaino EC (1982) Combined vitamin D parathyroid defect in thalassemia major. Arch Intern Med 142:831–832PubMedCrossRefGoogle Scholar
  70. 70.
    de Vernejoul MC, Girot R, Gueris J, Cancela L, Bang S, Bielakoff J, Mautalen C, Goldberg D, Miravet L (1982) Calcium phosphate metabolism and bone disease in patients with homozygous thalassemia. J Clin Endocrinol Metab 54:276–281PubMedCrossRefGoogle Scholar
  71. 71.
    Napoli N, Carmina E, Bucchieri S, Sferrazza C, Rini GB, Di Fede G (2006) Low serum levels of 25-hydroxyvitamin D in adults affected by thalassemia major or intermedia. Bone 38:888–892PubMedCrossRefGoogle Scholar
  72. 72.
    Zamboni G, Marradi P, Tagliaro F, Dorizzi R, Tato L (1986) Parathyroid hormone, calcitonin and vitamin D metabolites in beta-thalassaemia major. Eur J Pediatr 145:133–136PubMedCrossRefGoogle Scholar
  73. 73.
    Chapelon E, Garabedian M, Brousse V, Souberbielle JC, Bresson JL, de Montalembert M (2009) Osteopenia and vitamin D deficiency in children with sickle cell disease. Eur J Haematol 83:572–578PubMedCrossRefGoogle Scholar
  74. 74.
    Pratelli L, Verri E, Fortini M, Marconi S, Zolezzi C, Fornasari PM, Gamberini MR, De Sanctis V (2006) Chelation therapy and bone metabolism markers in thalassemia major. J Pediatr Endocrinol Metab 19:1335–1342PubMedCrossRefGoogle Scholar
  75. 75.
    Soliman A, Adel A, Wagdy M, Al Ali M, ElMulla N (2008) Calcium homeostasis in 40 adolescents with β-thalassemia major: a case-control study of the effects of intramuscular injection of a megadose of cholecalciferol. Pediatr Endocrinol Rev 6:149–154PubMedGoogle Scholar
  76. 76.
    Costin G, Kogut MD, Hyman CB, Ortega JA (1979) Endocrine abnormalities in thalassemia major. Am J Dis Child 133:497–502PubMedCrossRefGoogle Scholar
  77. 77.
    El-Nashar M, Mortagy AK, El-Beblawy NMS, El-Gohary E, Kamel IM, Rashad M, Mouharam WA (2017) Parathyroid hormone in pediatric patients with β-thalassemia major and its relation to bone mineral density; a case control study. Egypt J Med Hum Genet 18:75–78CrossRefGoogle Scholar
  78. 78.
    Jensen CE, Tuck SM, Old J, Morris RW, Yardumian A, De Sanctis V, Hoffbrand AV, Wonke B (1997) Incidence of endocrine complications and clinical disease severity related to genotype analysis and iron overload in patients with & #x03B2;-thalassaemia. Eur J Haematol 59:76–81PubMedCrossRefGoogle Scholar
  79. 79.
    Bouillon R, Van Cromphaut S, Carmeliet G (2003) Intestinal calcium absorption: molecular vitamin D mediated mechanisms. J Cell Biochem 88:332–339PubMedCrossRefGoogle Scholar
  80. 80.
    Van Cromphaut SJ, Rummens K, Stockmans I, Van Herck E, Dijcks FA, Ederveen AG, Carmeliet P, Verhaeghe J, Bouillon R, Carmeliet G (2003) Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D receptor-independent mechanisms. J Bone Miner Res 18:1725–1736PubMedCrossRefGoogle Scholar
  81. 81.
    Nemere I, Norman AW (1989) 1,25-Dihydroxyvitamin D3-mediated vesicular calcium transport in intestine: dose-response studies. Mol Cell Endocrinol 67:47–53PubMedCrossRefGoogle Scholar
  82. 82.
    Olson EB Jr, Deluca HF, Potts JT Jr (1972) Calcitonin inhibition of vitamin D-induced intestinal calcium absorption. Endocrinology 90:151–157PubMedCrossRefGoogle Scholar
  83. 83.
    Cramer CF (1973) Effect of salmon calcitonin on in vivo calcium absorption in rats. Calcif Tissue Res 13:169–172PubMedCrossRefGoogle Scholar
  84. 84.
    Swaminathan R, Ker J, Care D (1974) Calcitonin and intestinal calcium absorption. J Endocrinol 61:83–94PubMedCrossRefGoogle Scholar
  85. 85.
    Wongsurawat N, Armbrecht HJ (1991) Calcitonin stimulates 1,25-dihydroxyvitamin D production in diabetic rat kidney. Metabolism 40:22–25PubMedCrossRefGoogle Scholar
  86. 86.
    Canatan D, Akar N, Arcasoy A (1995) Effects of calcitonin therapy on osteoporosis in patients with thalassemia. Acta Haematol 93:20–24PubMedCrossRefGoogle Scholar
  87. 87.
    Lasco A, Morabito N, Gaudio A, Buemi M, Wasniewska M, Frisina N (2001) Effects of hormonal replacement therapy on bone metabolism in young adults with beta-thalassemia major. Osteoporos Int 12:570–575PubMedCrossRefGoogle Scholar
  88. 88.
    Tiosano D, Hochberg Z (2001) Endocrine complications of thalassemia. J Endocrinol Invest 24:716–723PubMedCrossRefGoogle Scholar
  89. 89.
    Colin EM, Van Den Bemd GJ, Van Aken M, Christakos S, De Jonge HR, Deluca HF, Prahl JM, Birkenhager JC, Buurman CJ, Pols HA, Van Leeuwen JP (1999) Evidence for involvement of 17β-estradiol in intestinal calcium absorption independent of 1,25-dihydroxyvitamin D3 level in the rat. J Bone Miner Res 14:57–64PubMedCrossRefGoogle Scholar
  90. 90.
    Bożentowicz-Wikarek M, Kocełak P, Owczarek A, Olszanecka-Glinianowicz M, Mossakowska M, Skalska A, Więcek A, Chudek J (2015) Plasma fibroblast growth factor 23 concentration and iron status. Does the relationship exist in the elderly population? Clin Biochem 48:431–436PubMedCrossRefGoogle Scholar
  91. 91.
    Hanudel MR, Chua K, Rappaport M, Gabayan V, Valore E, Goltzman D, Ganz T, Nemeth E, Salusky IB (2016) Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice. Am J Physiol Renal Physiol 311:F1369–F1377PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Wolf M, Koch TA, Bregman DB (2013) Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res 28:1793–1803PubMedCrossRefGoogle Scholar
  93. 93.
    Abdulzahra MS, Al-Hakeim HK, Ridha MM (2011) Study of the effect of iron overload on the function of endocrine glands in male thalassemia patients. Asian J Transfus Sci 5:127–131PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    de Montalembert M, Ribeil JA, Brousse V, Guerci-Bresler A, Stamatoullas A, Vannier JP, Dumesnil C, Lahary A, Touati M, Bouabdallah K, Cavazzana M, Chauzit E, Baptiste A, Lefebvre T, Puy H, Elie C, Karim Z, Ernst O, Rose C (2017) Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome. PLoS One 12:e0172147PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    De Sanctis V, Soliman AT, Elsedfy H, Albu A, Al Jaouni S, Anastasi S, Bisconte MG, Canatan D, Christou S, Daar S, Di Maio S, El Kholy M, Khater D, Elshinawy M, Kilinc Y, Mattei R, Mosli HH, Quota A, Roberti MG, Sobti P, Yaarubi SA, Canpisi S, Kattamis C (2017) Review and recommendations on management of adult female thalassemia patients with hypogonadism based on literature review and experience of ICET-A network specialists. Mediterr J Hematol Infect Dis 9:e2017001PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Gardenghi S, Ramos P, Follenzi A, Rao N, Rachmilewitz EA, Giardina PJ, Grady RW, Rivella S (2010) Hepcidin and Hfe in iron overload in β-thalassemia. Ann N Y Acad Sci 1202:221–225PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Jackson LH, Vlachodimitropoulou E, Shangaris P, Roberts TA, Ryan TM, Campbell-Washburn AE, David AL, Porter JB, Lythgoe MF, Stuckey DJ (2017) Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of β-thalassemia. Sci Rep. Google Scholar
  98. 98.
    Karami H, Kosaryan M, Amree AH, Darvishi-Khezri H, Mousavi M (2017) Combination iron chelation therapy with deferiprone and deferasirox in iron-overloaded patients with transfusion-dependent β-thalassemia major. Clin Pract 7:912PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Limenta LM, Jirasomprasert T, Jittangprasert P, Wilairat P, Yamanont P, Chantharaksri U, Fucharoen S, Morales NP (2011) Pharmacokinetics of deferiprone in patients with & #x03B2;-thalassaemia: impact of splenectomy and iron status. Clin Pharmacokinet 50:41–50CrossRefGoogle Scholar
  100. 100.
    Mishra AK, Tiwari A (2013) Iron overload in beta thalassaemia major and intermedia patients. Maedica (Buchar) 8:328–332Google Scholar
  101. 101.
    Musallam KM, Cappellini MD, Taher AT (2013) Iron overload in β-thalassemia intermedia: an emerging concern. Curr Opin Hematol 20:187–192PubMedCrossRefGoogle Scholar
  102. 102.
    Ramos P, Melchiori L, Gardenghi S, Van-Roijen N, Grady RW, Ginzburg Y, Rivella S (2010) Iron metabolism and ineffective erythropoiesis in & #x03B2;-thalassemia mouse models. Ann N Y Acad Sci 1202:24–30PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Fiorelli G, Fargion S, Piperno A, Battafarano N, Cappellini MD (1990) Iron metabolism in thalassemia intermedia. Haematologica 75:89–95PubMedGoogle Scholar
  104. 104.
    Taher AT, Porter J, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, Siritanaratkul N, Galanello R, Karakas Z, Lawniczek T, Ros J, Zhang Y, Habr D, Cappellini MD (2012) Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood 120:970–977PubMedCrossRefGoogle Scholar
  105. 105.
    Gardenghi S, Marongiu MF, Ramos P, Guy E, Breda L, Chadburn A, Liu Y, Amariglio N, Rechavi G, Rachmilewitz EA, Breuer W, Cabantchik ZI, Wrighting DM, Andrews NC, de Sousa M, Giardina PJ, Grady RW, Rivella S (2007) Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 109:5027–5035PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, Muirhead K, Rao N, Roy CN, Andrews NC, Nemeth E, Follenzi A, An X, Mohandas N, Ginzburg Y, Rachmilewitz EA, Giardina PJ, Grady RW, Rivella S (2010) Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice. J Clin Invest 120:4466–4477PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Weizer-Stern O, Adamsky K, Amariglio N, Rachmilewitz E, Breda L, Rivella S, Rechavi G (2006) mRNA expression of iron regulatory genes in β-thalassemia intermedia and β-thalassemia major mouse models. Am J Hematol 81:479–483PubMedCrossRefGoogle Scholar
  108. 108.
    Bartnikas TB, Fleming MD (2010) A tincture of hepcidin cures all: the potential for hepcidin therapeutics. J Clin Invest 120:4187–4190PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Wasserman RH, Chandler JS, Meyer SA, Smith CA, Brindak ME, Fullmer CS, Penniston JT, Kumar R (1992) Intestinal calcium transport and calcium extrusion processes at the basolateral membrane. J Nutr 122:662–671PubMedCrossRefGoogle Scholar
  110. 110.
    Moriya M, Linder MC (2006) Vesicular transport and apotransferrin in intestinal iron absorption, as shown in the Caco-2 cell model. Am J Physiol Gastrointest Liver Physiol 290:G301–G309PubMedCrossRefGoogle Scholar
  111. 111.
    Lloyd-Evans E (2016) On the move, lysosomal CAX drives Ca2+ transport and motility. J Cell Biol 212:755–757PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Wang L, Li Q, Duan XL, Chang YZ (2005) Effects of extracellular iron concentration on calcium absorption and relationship between Ca2+ and cell apoptosis in Caco-2 cells. World J Gastroenterol 11:2916–2921PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Merchant RH, Shirodkar A, Ahmed J (2011) Evaluation of growth, puberty and endocrine dysfunctions in relation to iron overload in multi transfused Indian thalassemia patients. Indian J Pediatr 78:679–683PubMedCrossRefGoogle Scholar
  114. 114.
    He YF, Ma Y, Gao C, Zhao GY, Zhang LL, Li GF, Pan YZ, Li K, Xu YJ (2013) Iron overload inhibits osteoblast biological activity through oxidative stress. Biol Trace Elem Res 152:292–296PubMedCrossRefGoogle Scholar
  115. 115.
    Klein GL, Snodgrass WR, Griffin MP, Miller NL, Alfrey AC (1989) Hypocalcemia complicating deferoxamine therapy in an infant with parenteral nutrition-associated aluminum overload: evidence for a role of aluminum in the bone disease of infants. J Pediatr Gastroenterol Nutr 9:400–403PubMedCrossRefGoogle Scholar
  116. 116.
    Chirico V, Lacquaniti A, Salpietro V, Luca N, Ferrau V, Piraino B, Rigoli L, Salpietro C, Arrigo T (2013) Thyroid dysfunction in thalassaemic patients: ferritin as a prognostic marker and combined iron chelators as an ideal therapy. Eur J Endocrinol 169:785–793PubMedCrossRefGoogle Scholar
  117. 117.
    Eshragi P, Tamaddoni A, Zarifi K, Mohammadhasani A, Aminzadeh M (2011) Thyroid function in major thalassemia patients: is it related to height and chelation therapy? Casp J Intern Med 2:189–193Google Scholar
  118. 118.
    Rombos Y, Tzanetea R, Konstantopoulos K, Simitzis S, Zervas C, Kyriaki P, Kavouklis M, Aessopos A, Sakellaropoulos N, Karagiorga M, Kalotychou V, Loukopoulos D (2000) Chelation therapy in patients with thalassemia using the orally active iron chelator deferiprone (L1). Haematologica 85(2):115–117PubMedGoogle Scholar
  119. 119.
    Fisher SA, Brunskill SJ, Doree C, Chowdhury O, Gooding S, Roberts DJ (2013) Oral deferiprone for iron chelation in people with thalassaemia. Cochrane Database Syst Rev CD004839Google Scholar
  120. 120.
    Fisher SA, Brunskill SJ, Doree C, Gooding S, Chowdhury O, Roberts DJ (2013) Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. Cochrane Database Syst Rev CD004450Google Scholar
  121. 121.
    Rodrat M, Wongdee K, Panupinthu N, Thongbunchoo J, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N (2018) Prolonged exposure to 1,25(OH)2D3 and high ionized calcium induces FGF-23 production in intestinal epithelium-like Caco-2 monolayer: a local negative feedback for preventing excessive calcium transport. Arch Biochem Biophys 640:10–16PubMedCrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Kornkamon Lertsuwan
    • 1
    • 2
  • Kannikar Wongdee
    • 2
    • 3
  • Jarinthorn Teerapornpuntakit
    • 2
    • 4
  • Narattaphol Charoenphandhu
    • 2
    • 5
    • 6
  1. 1.Department of Biochemistry, Faculty of ScienceMahidol UniversityBangkokThailand
  2. 2.Center of Calcium and Bone Research (COCAB), Faculty of ScienceMahidol UniversityBangkokThailand
  3. 3.Office of Academic Management, Faculty of Allied Health SciencesBurapha UniversityChonburiThailand
  4. 4.Department of Physiology, Faculty of Medical ScienceNaresuan UniversityPhitsanulokThailand
  5. 5.Department of Physiology, Faculty of ScienceMahidol UniversityBangkokThailand
  6. 6.Institute of Molecular Biosciences, Mahidol UniversityNakhon PathomThailand

Personalised recommendations