Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin

Sara Gardenghi, Maria F. Marongiu, Pedro Ramos, Ella Guy, Laura Breda, Amy Chadburn, Yi Fang Liu, Ninette Amariglio, Gideon Rechavi, Eliezer A. Rachmilewitz, William Breuer, Z. Ioav Cabantchik, Diedra M. Wrighting, Nancy C. Andrews, Maria De Sousa, Patricia J. Giardina, Robert W. Grady, Stefano Rivella*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Progressive iron overload is the most salient and ultimately fatal complication of β-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in β-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 β-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 β-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 β-thalassemia.

Original languageEnglish
Pages (from-to)5027-5035
Number of pages9
JournalBlood
Volume109
Issue number11
DOIs
StatePublished - 1 Jun 2007

Funding

FundersFunder number
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK055463

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