Blood Journal
Leading the way in experimental and clinical research in hematology

Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells

  1. Toshihiko Tanno1,
  2. Prashanth Porayette2,
  3. Orapan Sripichai1,
  4. Seung-Jae Noh1,
  5. Colleen Byrnes1,
  6. Ajoy Bhupatiraju1,
  7. Y. Terry Lee1,
  8. Julia B. Goodnough3,
  9. Omid Harandi2,
  10. Tomas Ganz3,
  11. Robert F. Paulson2, and
  12. Jeffery L. Miller1
  1. 1Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD;
  2. 2Department of Veterinary and Biomedical Sciences, Center of Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park; and
  3. 3Departments of Medicine and Pathology, University of California, Los Angeles

Abstract

In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative polymerase chain reaction (PCR) in dosed assays (1-1000 ng/mL TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin up-regulation by bone morphogenic proteins 2 and 4 (BMP2/BMP4). In murine hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.

  • Submitted December 24, 2008.
  • Accepted April 22, 2009.
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