Gardenghi Sara, Marongiu Maria F, Ramos Pedro, Guy Ella, Breda Laura, Chadburn Amy, Liu YiFang, Amariglio Ninette, Rechavi Gideon, Rachmilewitz Eliezer A, Breuer William, Cabantchik Z Ioav, Wrighting Diedra M, Andrews Nancy C, de Sousa Maria, Giardina Patricia J, Grady Robert W, Rivella Stefano
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.
Blood. 2007 Jun 1;109(11):5027-35. doi: 10.1182/blood-2006-09-048868. Epub 2007 Feb 13.
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.
进行性铁过载是β地中海贫血最显著且最终致命的并发症。然而，关于β地中海贫血中无效红细胞生成（IE）、铁调节基因的作用以及组织铁分布之间的关系，我们所知甚少。我们分析了年龄高达1岁的小鼠肝脏、十二指肠、脾脏、骨髓、肾脏和心脏中的组织铁含量以及铁调节基因表达，这些小鼠表现出与中间型β地中海贫血（th3/+）和重型β地中海贫血（th3/th3）一致的铁过载和贫血水平。在此我们首次表明，th3/+和th3/th3小鼠的组织和细胞铁分布存在异常且不同，并且输血治疗可以挽救受重型β地中海贫血影响的小鼠，并改变铁的吸收和分布。我们的研究表明，IE的程度决定了组织铁分布，并且IE和铁含量调节铁调素（Hamp1）以及其他铁调节基因，如Hfe和Cebpa。在年轻的th3/+和th3/th3小鼠中，低水平的Hamp1导致铁吸收增加。然而，在1岁的th3/+动物中，Hamp1水平升高，而正是铁转运蛋白（Fpn1）的增加维持了铁的积累，从而揭示了这种铁转运蛋白在β地中海贫血铁过载中的重要作用。
