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High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin

Nature Medicine volume 13, pages 1096–1101 (2007)Cite this article

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-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.

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Figure 1: Transcriptional profiling of TGFB superfamily members during erythropoiesis.
Figure 2: GDF15 concentration in human blood and correlation with concentrations of hemoglobin, erythropoietin, soluble transferrin receptor and ferritin in blood from thalassemia patients.
Figure 3: Regulation of hepcidin mRNA expression by GDF15.
Figure 4

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Acknowledgements

The National Institutes of Health Department of Transfusion Medicine, National Institute of Diabetes and Digestive and Kidney Diseases Microarray Core Laboratory, and S. Strom, J. Goodnough, G. Moser and M. Ehinger performed or assisted with studies involving hepatocytes and transgenic mice. We thank C. Deng, C. Philpott, and A. Schechter for critical reading of the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations

  1. Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, 20892, Maryland, USA

    Toshihiko Tanno, Natarajan V Bhanu, Patricia A Oneal, Sung-Ho Goh, Pamela Staker, Y Terry Lee & Jeffery L Miller

  2. Department of Obstetrics and Gynecology, National Naval Medical Center, 8901 Rockville Pike, Bethesda, 20889, Maryland, USA

    John W Moroney & Christopher H Reed

  3. Laboratory Medicine and Pathology, Children's National Medical Center, 111 Michigan Ave. NW, Washington, 20010, DC, USA

    Naomi LC Luban

  4. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, 20892, Maryland, USA

    Rui-Hong Wang

  5. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, 27709, North Carolina, USA

    Thomas E Eling

  6. Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Richard Childs

  7. Departments of Medicine and Pathology, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, 90095, California, USA

    Tomas Ganz

  8. Department of Transfusion Medicine, National Institutes of Health, 10 Center Drive, Bethesda, 20892, Maryland, USA

    Susan F Leitman

  9. Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya, Phuttamonthon 4 Rd., Phuttamonthon, 73170, Nakornpathom, Thailand

    Suthat Fucharoen

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  1. Toshihiko Tanno
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Contributions

T. T., manuscript writing, performed experiments, assembly of data. N.V.B., collection and assembly of array data. P.A.O., collection of clinical samples and data. S.-H.G., provision of study material, array data analysis. P.S., collection of clinical samples and data. Y.T.L., collection and assembly of array data. J.W.M., collection of clinical samples. C.H.R., collection of clinical samples and data. N.L.C.L., collection of clinical samples and data. R.-H.W., expertise with hepatic iron assessment. T.E., expertise with GDF15 transgenic mouse. R.C., collection of clinical samples and data. T.G., mouse GDF15 analyses, manuscript revision. S.F.L., collection of clinical samples and data. S.F., collection of clinical samples and data. J.L.M., manuscript writing, experimental conception and design, assisted and supervised research team.

Corresponding author

Correspondence to Jeffery L Miller.

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A provisional patent (Application No. 601864.705) was generated on the basis of these findings.

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Tanno, T., Bhanu, N., Oneal, P. et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13, 1096–1101 (2007). https://doi.org/10.1038/nm1629

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