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Title: High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin
Authors: Toshihiko Tanno
Natarajan V. Bhanu
Patricia A. Oneal
Sung Ho Goh
Pamela Staker
Y. Terry Lee
John W. Moroney
Christopher H. Reed
Naomi L.C. Luban
Rui Hong Wang
Thomas E. Eling
Richard Childs
Tomas Ganz
Susan F. Leitman
Suthat Fucharoen
Jeffery L. Miller
National Institute of Diabetes and Digestive and Kidney Diseases
Walter Reed National Military Medical Center
Childrens National Health System
National Institute of Environmental Health Sciences
National Heart, Lung, and Blood Institute
David Geffen School of Medicine at UCLA
National Institutes of Health, Bethesda
The Institute of Science and Technology for Research and Development, Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Sep-2007
Citation: Nature Medicine. Vol.13, No.9 (2007), 1096-1101
Abstract: In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 ± 50 pg/ml. In comparison, individuals with β-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 ± 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression. © 2007 Nature Publishing Group.
ISSN: 1546170X
Appears in Collections:Scopus 2006-2010

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