The pathophysiology and pharmacology of hepcidin

Abstract

Inappropriate production of the iron-regulatory hormone hepcidin contributes to the pathogenesis of common iron disorders. Absolute or relative deficiency of hepcidin causes iron overload in hereditary hemochromatosis and iron-loading anemias. Elevated hepcidin causes iron restriction in inflammatory conditions including autoimmune disease, critical illness, some cancers, and chronic kidney disease. Multiple agents targeting hepcidin and its regulators are under development as novel therapeutics for iron disorders. This review summarizes hepcidin biology and discusses the current landscape for hepcidin-targeting therapeutic strategies.

Keywords: anemia; ferroportin; iron disorders; iron overload.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. The role of hepcidin in iron metabolism

Hepcidin-ferroportin interaction determines the flow of iron into plasma. Hepcidin concentration is in turn regulated by iron, erythropoietic activity, and inflammation. Republished with permission from Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010 Dec 2;116(23):4754–61. © the American Society of Hematology.

Figure 2. Regulation of hepcidin transcription

(A) Hepcidin regulation by extracellular iron. The BMP/Smad pathway is central to the transcriptional regulation of hepcidin expression. The BMP pathway signaling is further modulated by hemojuvelin (HJV), a BMP co-receptor. The sensing of holotransferrin is proposed to occur through the following mechanism: binding of holo-transferrin (Fe-Tf) to TfR1 displaces HFE from the complex with TfR1 and promotes its interaction with TfR2. TfR2 protein is itself stabilized by the binding of Fe-Tf. The HFE/TfR2 may promote BMP signaling by forming a complex with HJV, or even acting independently of HJV or each other. Additional proteins (TMPRSS6/matriptase-2 (MT2) and neogenin) modulate the cleavage of membrane HJV and thus alter hepcidin transcription. (B) Hepcidin regulation by inflammation. IL-6 and other cytokines (e.g. oncostatin M, IL-22) were shown to regulate hepcidin expression by activating the Stat3 pathway. Activin B acting via BMP receptors and the Smad1/5/8 pathway was also proposed to stimulate hepcidin expression during inflammation.