title: Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin.
abstract: Progressive iron overload is the most salient and ultimately fatal complication of beta-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both beta-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3/th3 mice, and that transfusion therapy can rescue mice affected by beta-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as Hfe and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of beta-thalassemia.
authors.affiliation: Department of Pediatric Hematology-Oncology, Children's Blood Foundation Laboratories, Weill Medical College of Cornell University, 515E 71st Street S702, New York, NY 10021, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Gardenghi
authors.forename: Maria F
authors.initials: MF
authors.lastname: Marongiu
authors.forename: Pedro
authors.initials: P
authors.lastname: Ramos
authors.forename: Ella
authors.initials: E
authors.lastname: Guy
authors.forename: Laura
authors.initials: L
authors.lastname: Breda
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: YiFang
authors.initials: Y
authors.lastname: Liu
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Eliezer A
authors.initials: EA
authors.lastname: Rachmilewitz
authors.forename: William
authors.initials: W
authors.lastname: Breuer
authors.forename: Z Ioav
authors.initials: ZI
authors.lastname: Cabantchik
authors.forename: Diedra M
authors.initials: DM
authors.lastname: Wrighting
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
authors.forename: Maria
authors.initials: M
authors.lastname: de Sousa
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Giardina
authors.forename: Robert W
authors.initials: RW
authors.lastname: Grady
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D001803:Blood Transfusion; D027682:Cation Transport Proteins / Q000096:biosynthesis*; D015536:Down-Regulation; D004920:Erythropoiesis; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D064451:Hepcidins; D007501:Iron / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D015854:Up-Regulation; D017086:beta-Thalassemia / Q000097:blood* / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron