Letter abstract
Nature Medicine 13, 1096 - 1101 (2007)
Published online: 26 August 2007 | doi:10.1038/nm1629
High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin
Toshihiko Tanno1, Natarajan V Bhanu1, Patricia A Oneal1, Sung-Ho Goh1, Pamela Staker1, Y Terry Lee1, John W Moroney2, Christopher H Reed2, Naomi LC Luban3, Rui-Hong Wang4, Thomas E Eling5, Richard Childs6, Tomas Ganz7, Susan F Leitman8, Suthat Fucharoen9 & Jeffery L Miller1
Abstract
In thalassemia, deficient globin-chain production during erythropoiesis results in anemia1, 2, 3. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death4. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism5. 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-
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 -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.
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
- Department of Obstetrics and Gynecology, National Naval Medical Center, 8901 Rockville Pike, Bethesda, Maryland 20889, USA.
- Laboratory Medicine and Pathology, Children's National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010, USA.
- Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
- Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Departments of Medicine and Pathology, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095, USA.
- Department of Transfusion Medicine, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
- Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya, Phuttamonthon 4 Rd., Phuttamonthon, Nakornpathom 73170, Thailand.
Correspondence to: Jeffery L Miller1 e-mail: jm7f@nih.gov
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