Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation - PubMed (original) (raw)

Review

. 2012 Apr;87(4):392-400.

doi: 10.1002/ajh.23110. Epub 2012 Jan 31.

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Review

Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation

Chia Chi Sun et al. Am J Hematol. 2012 Apr.

Abstract

Anemia of chronic disease (ACD) or anemia of inflammation is prevalent in patients with chronic infection, autoimmune disease, cancer, and chronic kidney disease. ACD is associated with poor prognosis and lower quality of life. Management of ACD using intravenous iron and erythropoiesis stimulating agents are ineffective for some patients and are not without adverse effects, driving the need for new alternative therapies. Recent advances in our understanding of the molecular mechanisms of iron regulation reveal that increased hepcidin, the iron regulatory hormone, is a key factor in the development of ACD. In this review, we will summarize the role of hepcidin in iron homeostasis, its contribution to the pathophysiology of ACD, and novel strategies that modulate hepcidin and its target ferroportin for the treatment of ACD.

Copyright © 2012 Wiley Periodicals, Inc.

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Figures

Figure 1

Figure 1. Hepcidin regulation by BMP6-HJV-SMAD and IL-6-STAT3 signaling pathways

The BMP6-HJV-SMAD and IL-6-STAT3 signaling pathways both activate hepcidin transcription in the liver (black arrows). In response to iron sufficiency, circulating bone morphogenetic protein 6 (BMP6) binds transmembrane BMP receptors type I (BMP-RI) and type II (BMP-RII) and BMP co-receptor hemojuvelin (HJV) to create a multiplex on the hepatocyte membrane to activate the SMAD signaling cascade. Activated intracellular SMAD1/5/8 proteins then complex with the common mediator SMAD4 and translocate to the nucleus to induce hepcidin expression through BMP- responsive elements (BMP-REs) localized on the hepcidin promoter. In an inflammatory setting, pro-inflammatory cytokines like IL-6 are released. Upon binding to its receptor, IL-6 initiates signaling through activated JAK1/2 proteins to phosphorylate the transcription factor STAT3. Activated STAT3 then binds to a STAT3-responsive element (STAT3-RE) on the proximal hepcidin promoter. Both STAT3-RE and the adjacent BMPR-RE are required for IL-6 mediated hepcidin expression. Hepcidin protein is secreted into the bloodstream to result in ferroportin inhibition, leading to iron retention in the reticuloendothelial macrophages and reduced iron absorption in the intestinal epithelia.

Figure 2

Figure 2. Inhibitors that target the hepcidin-ferroportin axis are potential therapeutic avenues for treating ACD

Since excess hepcidin leads to ACD, blocking the signaling pathways responsible for hepcidin synthesis, neutralizing hepcidin's effect on ferroportin or promoting ferroportin function may ameliorate ACD (red lines). Hepcidin production can be effectively inhibited by the following BMP6-HJV-SMAD inhibitors: soluble HJV.Fc protein (Ferrumax Pharmaceuticals), monoclonal anti-BMP6 antibodies, or the glycosaminoglycan heparin sequester BMP6, preventing its interaction with BMPR and membrane anchored HJV; the dorsomophin derivative LDN-193189 inhibits BMP type I receptor activity. Alcohol may also inhibit hepcidin synthesis by dampening the BMP-SMAD pathway. Anti-inflammatory therapeutics suppress IL-6 mediated hepcidin gene expression by: blocking antibody to IL-6 Siltuximab (Janssen Biotech Inc); neutralizing antibody to IL-6 receptor Tocilizumab (Genentech); or STAT3 pathway inhibitors, which block the phosphorylation of STAT3 (AG490) or its transcription factor binding activity (PpYLKTK). Vitamin D can also downregulate hepcidin transcription but the mechamism is unknown. Hepcidin protein expression or activity may be inhibited directly by: hepcidin siRNA [106]; hepcidin anti-sense oligonucleotides (Xenon Pharmaceuticals and ISIS Pharmaceuticals); or direct hepcidin antagonists, including anti-hepcidin antibodies (Amgen, Eli Lilly), hepcidin sequestering anticalins (Pieris AG) or hepcidin binding spiegelmers (NOXXON Pharma). Ferroportin agonists/ stabilizers, which modify the ferroportin-hepcidin interaction or increase ferroportin's resistance to hepcidin (Eli-Lilly), may theoretically ameliorate anemia by maintaining ferroportin activity and allowing iron influx.

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