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Review
. 2013 Nov;98(11):1667-76.
doi: 10.3324/haematol.2013.084624.

Manipulation of the hepcidin pathway for therapeutic purposes

Eileen Fung  1 , Elizabeta Nemeth
Affiliations
Review

Manipulation of the hepcidin pathway for therapeutic purposes

Eileen Fung et al. Haematologica. 2013 Nov.

Abstract

Hepcidin, the liver-produced peptide hormone, is a principal regulator of iron homeostasis. Abnormal hepcidin production has emerged as a causative factor in several common iron disorders. Hepcidin insufficiency results in iron overload in hereditary hemochromatosis and iron-loading anemias, whereas hepcidin excess causes or contributes to the development of iron-restricted anemias in inflammatory diseases, infections, some cancers and chronic kidney disease. Not surprisingly, hepcidin and related pathways have become the target for the development of novel therapeutics for iron disorders. In this review, we will summarize the strategies and development programs that have been devised for agonizing or antagonizing hepcidin and its receptor ferroportin.

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Figures

Figure 1.
Figure 1.
Pathways regulating hepcidin expression. (A) Hepcidin regulation by iron. Binding of holo-transferrin (Fe-Tf) to TfR1 displaces HFE from the complex with TfR1. HFE then interacts with TfR2, which is itself stabilized by the binding of Fe-Tf. The HFE/TfR2 is thought to form a complex with hemojuvelin (HJV), a BMP co-receptor. The BMP pathway is consequently stimulated, resulting in the phosphorylation of Smad1/5/8 and an increase in hepcidin transcription. Additional proteins (TMPRSS6/matriptase-2 (MT2) and neogenin) mediate the cleavage of membrane HJV and thus modulate hepcidin transcription. (B) Hepcidin regulation by inflammation. During inflammation, IL-6 and other cytokines (e.g. oncostatin M, IL-22) activate the Stat3 pathway to promote transcription of hepcidin. Activin B acting via BMP receptors and the Smad1/5/8 pathway was also proposed to stimulate hepcidin expression during inflammation.
Figure 2.
Figure 2.
The role of hepcidin in the pathogenesis of iron disorders. (A) Normal iron homeostasis: hepcidin modulates iron flows into plasma from splenic and liver macrophages, hepatocytes and the duodenum to maintain relatively constant plasma iron concentrations. Most of the plasma iron is utilized by erythroid precursors in the bone marrow to synthesize hemoglobin. This iron is eventually recycled from old red blood cells by erythrophagocytosing macrophages. (B) Iron overload: hepcidin insufficiency causes iron overload in hereditary hemochromatosis and iron-loading anemias. In hereditary hemochromatosis, hepcidin production is low because of inactivating mutations in the genes encoding hepcidin or its regulators. In iron-loading anemias, hepcidin is suppressed by the high erythropoietic drive, via as yet poorly understood mechanisms. In either disease, low hepcidin allows excessive iron absorption and rapid release of recycled iron from macrophages. Plasma iron levels increase, non-transferrin-bound iron (NTBI) accumulates, and excess iron is deposited in vital organs where it causes organ damage. (C) Iron-restricted anemias: hepcidin is elevated in inflammatory disorders, certain cancers and chronic kidney disease because proinflammatory cytokines stimulate hepcidin transcription. In kidney diseases, decreased renal clearance of hepcidin may also contribute. In iron-refractory iron deficiency anemia, hepcidin is increased because of the mutations in TMPRSS6, a negative regulator of hepcidin. In all of these conditions, elevated hepcidin inhibits iron efflux from macrophages, hepatocytes and the duodenum. As a result, hypoferremia develops and erythropoiesis becomes iron-limited, eventually manifesting as anemia.
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