Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. We have recently discovered that the bone morphogenetic protein (BMP) signaling pathway plays an important role in systemic iron balance by modulating expression of the iron regulatory hormone hepcidin. A soluble protein secreted by the liver, hepcidin acts by downregulating the cell- surface expression of the iron exporter ferroportin to control iron absorption from the diet and iron release from body stores. Hepcidin deficiency, which causes excessive dietary iron absorption and progressive tissue iron deposition and dysfunction, appears to be the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis due to mutations in the genes encoding hepcidin itself, the hemochromatosis protein HFE, transferrin receptor 2, and hemojuvelin (HJV). Although the mechanism(s) by which HFE and transferrin receptor 2 regulate hepcidin expression remain uncertain, we have recently discovered that HJV is a BMP co-receptor and that BMP-HJV-SMAD signals regulate hepcidin expression and systemic iron balance in vivo. Here, we show that HJV binds BMP6, and that Bmp6-/- mice have a hemochromatosis phenotype resembling Hjv-/- mice, suggesting that BMP6 a key endogenous ligand for HJV that is necessary for regulating hepcidin expression and iron metabolism in vivo. We also show that dietary iron modulates BMP6 expression concordantly with hepcidin expression, suggesting that regulation of BMP6 expression may be one mechanism by which iron modulates hepcidin expression. Finally, we show that Hfe-/- mice have appropriately increased Bmp6 levels, but inappropriately low expression of downstream signaling targets of Bmp6, suggesting that HFE may interact with the BMP6-HJV-SMAD signaling cascade to regulate hepcidin expression.
In Specific Aim I, we will use in vitro and in vivo approaches to determine the mechanism by which iron upregulates BMP6 expression.
In Aim II, we will use iodinated protein-interaction and Biacore binding assays to dissect the protein-interaction domains that allow BMP6 and its co-receptor HJV to interact to enhance SMAD signaling and hepcidin expression.
In Aim III, we will use biochemical assays, cell culture models, Hfe-/- mice, and Hfe transgenic mice to investigate whether HFE interacts with the BMP6-HJV-SMAD signaling cascade to regulate hepcidin expression. The long-term goal of this project is to understand the role of the BMP signaling pathway in regulating systemic iron homeostasis. It is hoped that this work may lead to new therapeutic strategies for treating disorders of iron metabolism such as anemia of chronic disease and hemochromatosis.

Public Health Relevance

Disorders of systemic iron balance represent a significant public health problem affecting over one billion people worldwide. This proposal will investigate a novel regulatory pathway that plays a key role in systemic iron balance. It is hoped that this work will lead to new treatments for disorders of iron overload such as hemochromatosis and disorders of iron deficiency such as anemia of chronic disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Erythrocyte and Leukocyte Biology Study Section (ELB)
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Bishop, Terry Rogers
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Massachusetts General Hospital
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Meynard, Delphine; Babitt, Jodie L; Lin, Herbert Y (2014) The liver: conductor of systemic iron balance. Blood 123:168-76
Core, Amanda B; Canali, Susanna; Babitt, Jodie L (2014) Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front Pharmacol 5:104
Zumbrennen-Bullough, Kimberly B; Wu, Qifang; Core, Amanda B et al. (2014) MicroRNA-130a is up-regulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription. J Biol Chem 289:23796-808
Zumbrennen-Bullough, Kimberly; Babitt, Jodie L (2014) The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients. Nephrol Dial Transplant 29:263-73
Babitt, Jodie L; Lin, Herbert Y (2014) BuMPing iron with modified heparins. Blood 123:1440-1
Sun, Chia Chi; Vaja, Valentina; Chen, Shanzhuo et al. (2013) A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. Nephrol Dial Transplant 28:1733-43
Chen, Wenjie; Sun, Chia Chi; Chen, Shanzhuo et al. (2013) A novel validated enzyme-linked immunosorbent assay to quantify soluble hemojuvelin in mouse serum. Haematologica 98:296-304
Sun, Chia Chi; Vaja, Valentina; Babitt, Jodie L et al. (2012) Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol 87:392-400
Babitt, Jodie L; Lin, Herbert Y (2011) The molecular pathogenesis of hereditary hemochromatosis. Semin Liver Dis 31:280-92
Meynard, Delphine; Vaja, Valentina; Sun, Chia Chi et al. (2011) Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 118:747-56

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