title: Hepcidin and 1,25(OH)2D3 effectively restore Ca2+ transport in β-thalassemic mice: reciprocal phenomenon of Fe2+ and Ca2+ absorption.
abstract: Previously, β-thalassemia, an inherited anemic disorder with iron overload caused by loss-of-function mutation of β-globin gene, has been reported to induce osteopenia and impaired whole body calcium metabolism, but the pathogenesis of aberrant calcium homeostasis remains elusive. Herein, we investigated how β-thalassemia impaired intestinal calcium absorption and whether it could be restored by administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or hepcidin, the latter of which was the liver-derived antagonist of intestinal iron absorption. The results showed that, in hemizygous β-globin knockout (BKO) mice, the duodenal calcium transport was lower than that in wild-type littermates, and severity was especially pronounced in female mice. Both active and passive duodenal calcium fluxes in BKO mice were found to be less than those in normal mice. This impaired calcium transport could be restored by 7-day 1,25(OH)2D3 treatment. The 1,25(OH)2D3-induced calcium transport was diminished by inhibitors of calcium transporters, e.g., L-type calcium channel, NCX1, and PMCA1b, as well as vesicular transport inhibitors. Interestingly, the duodenal calcium transport exhibited an inverse correlation with transepithelial iron transport, which was markedly enhanced in thalassemic mice. Thus, 3-day subcutaneous hepcidin injection and acute direct hepcidin exposure in the Ussing chamber were capable of restoring the thalassemia-associated impairment of calcium transport; however, the positive effect of hepcidin on calcium transport was completely blocked by proteasome inhibitors MG132 and bortezomib. In conclusion, both 1,25(OH)2D3 and hepcidin could be used to alleviate the β-thalassemia-associated impairment of calcium absorption. Therefore, our study has shed light on the development of a treatment strategy to rescue calcium dysregulation in β-thalassemia.
authors.affiliation: Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
authors.forename: Kamonshanok
authors.initials: K
authors.lastname: Kraidith
authors.affiliation: Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand; and.
authors.forename: Saovaros
authors.initials: S
authors.lastname: Svasti
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
authors.forename: Jarinthorn
authors.initials: J
authors.lastname: Teerapornpuntakit
authors.affiliation: Cell and Gene Therapy Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Jim
authors.initials: J
authors.lastname: Vadolas
authors.affiliation: Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
authors.forename: Rattana
authors.initials: R
authors.lastname: Chaimana
authors.affiliation: Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
authors.forename: Sarawut
authors.initials: S
authors.lastname: Lapmanee
authors.affiliation: Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand;
authors.forename: Panan
authors.initials: P
authors.lastname: Suntornsaratoon
authors.affiliation: Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand;
authors.forename: Nateetip
authors.initials: N
authors.lastname: Krishnamra
authors.affiliation: Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand; and.
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.affiliation: Center of Calcium and Bone Research, Faculty of Science, Mahidol University, Bangkok, Thailand; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; naratt@narattsys.com.
authors.forename: Narattaphol
authors.initials: N
authors.lastname: Charoenphandhu
mesh_terms: D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D057898:Hemizygote; D064451:Hepcidins / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D007501:Iron / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors; D055544:beta-Globins / Q000235:genetics; D017086:beta-Thalassemia / Q000235:genetics / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D015853:Cysteine Proteinase Inhibitors; D064451:Hepcidins; D007976:Leupeptins; C499849:NCX1 protein, mouse; C556012:Pmca1b protein, mouse; D019831:Sodium-Calcium Exchanger; D033921:Vesicular Transport Proteins; D055544:beta-Globins; D000069286:Bortezomib; D007501:Iron; D053499:Plasma Membrane Calcium-Transporting ATPases; D002117:Calcitriol; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D002118:Calcium
keywords: 1,25-dihydroxyvitamin D3; calcium malabsorption; calcium transporter; iron transport; thalassemia; vitamin D