Abstract
Iron overload results in significant morbidity and mortality in β-thalassemic patients. Insufficient hepcidin is implicated in parenchymal iron overload in β-thalassemia and approaches to increase hepcidin have therapeutic potential. We have previously shown that exogenous apo-transferrin markedly ameliorates ineffective erythropoiesis and increases hepcidin expression in Hbb(th1/th1) (thalassemic) mice. We utilize in vivo and in vitro systems to investigate effects of exogenous apo-transferrin on Smad and ERK1/2 signaling, pathways that participate in hepcidin regulation. Our results demonstrate that apo-transferrin increases hepcidin expression in vivo despite decreased circulating and parenchymal iron concentrations and unchanged liver Bmp6 mRNA expression in thalassemic mice. Hepatocytes from apo-transferrin-treated mice demonstrate decreased ERK1/2 pathway and increased serum BMP2 concentration and hepatocyte BMP2 expression. Furthermore, hepatocyte ERK1/2 phosphorylation is enhanced by neutralizing anti-BMP2/4 antibodies and suppressed in vitro in a dose-dependent manner by BMP2, resulting in converse effects on hepcidin expression, and hepatocytes treated with MEK/ERK1/2 inhibitor U0126 in combination with BMP2 exhibit an additive increase in hepcidin expression. Lastly, bone marrow erythroferrone expression is normalized in apo-transferrin treated thalassemic mice but increased in apo-transferrin injected wild-type mice. These findings suggest that increased hepcidin expression after exogenous apo-transferrin is in part independent of erythroferrone and support a model in which apo-transferrin treatment in thalassemic mice increases BMP2 expression in the liver and other organs, decreases hepatocellular ERK1/2 activation, and increases nuclear Smad to increase hepcidin expression in hepatocytes.
Copyright© Ferrata Storti Foundation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / pharmacology
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Apoproteins / pharmacology*
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Bone Morphogenetic Protein 2 / agonists
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Bone Morphogenetic Protein 2 / antagonists & inhibitors
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Bone Morphogenetic Protein 2 / genetics*
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Bone Morphogenetic Protein 2 / metabolism
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Bone Morphogenetic Protein 6 / genetics
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Bone Morphogenetic Protein 6 / metabolism
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Butadienes / pharmacology
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Cytokines / genetics
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Cytokines / metabolism
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Disease Models, Animal
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Gene Expression Regulation
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Hepcidins / agonists
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Hepcidins / antagonists & inhibitors
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Hepcidins / genetics*
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Hepcidins / metabolism
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Humans
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Liver / drug effects
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Liver / metabolism
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / genetics*
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Mitogen-Activated Protein Kinase 3 / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Nitriles / pharmacology
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Phosphorylation / drug effects
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction
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Smad Proteins / genetics
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Smad Proteins / metabolism
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Transferrin / pharmacology*
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beta-Thalassemia / genetics*
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beta-Thalassemia / metabolism
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beta-Thalassemia / pathology
Substances
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Antibodies, Neutralizing
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Apoproteins
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Bmp2 protein, mouse
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Bmp6 protein, mouse
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Protein 6
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Butadienes
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Cytokines
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Erfe protein, mouse
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Hamp protein, mouse
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Hepcidins
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Muscle Proteins
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Nitriles
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RNA, Messenger
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Smad Proteins
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Transferrin
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U 0126
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apotransferrin
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Mapk1 protein, mouse
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3