Iron is required for numerous functions in the human body. However, iron utilization in biological systems is challenging because of its intrinsic ability to generate reactive oxygen species Citation[1]. The majority of iron in the human body is used for erythropoiesis and is recycled to plasma transferrin through macrophage-mediated removal of senescent erythrocytes. Systems to remove excess iron from the body do not exist Citation[1]. Minor iron losses are balanced by dietary iron absorption in duodenal enterocytes. Excess absorption is prevented by the regulation of the hepatic peptide hormone, hepcidin (HAMP). HAMP limits plasma iron release by binding to ferroportin (FPN), an iron efflux surface protein present on macrophages, enterocytes and hepatocytes. Binding ultimately results in degradation of FPN Citation[1]. Thus, HAMP is the principal regulator of plasma iron concentration and is transcriptionally responsive to iron through the bone morphogenetic protein (BMP)/SMAD pathway Citation[2]. BMP-mediated HAMP induction is fine-tuned by the BMP coreceptor hemojuvelin (HJV), transferrin receptor 2 (TFR2) and HFE (the hemochromatosis protein), which together are thought to serve as the holotransferrin sensor, as well as two proteases, furin and matriptase-2 Citation[1,2]. HAMP is also upregulated by inflammation through activation of the JAK/STAT pathway mediated by IL-6, IL-1 and oncostatin M Citation[3,4]. HAMP is suppressed by anemia, hypoxia and erythropoiesis; however, the mechanisms are not completely understood Citation[5]. The existence of an undefined soluble factor released by the bone marrow and/or erythroblasts to communicate an erythropoietic need to the liver has been hypothesized. In the case of ineffective erythropoiesis (IE), a pathologically compromised ability to produce mature erythrocytes despite a massive increase in precursor cells, growth differentiation factor 15 and twisted gastrulation homolog 1 have been identified as potential candidates Citation[6–8]. Further studies are required to determine the precise molecular mechanism responsible for erythropoietic suppression of HAMP.
Iron overloading due to IE is a component of several disorders, including β-thalassemia Citation[7]. β-thalassemia is a genetic disease characterized by reduced or absent synthesis of β-globin. Patients with the most severe form, β-thalassemia major or Cooley’s anemia, require lifelong blood transfusions whereas those with a milder form, β-thalassemia intermedia, may be able to survive with limited or no transfusions Citation[9]. The defect in β-globin synthesis generates chronic anemia, which exacerbates IE and promotes extramedullary hematopoiesis, splenomegaly and iron overload Citation[9]. Myocardial disease secondary to iron overload is one of the predominant causes of mortality in β-thalassemia. Blood transfusion and iron chelation therapy are currently the primary strategies to treat β-thalassemia. Bone marrow transplant is an effective cure in select cases. Gene therapy approaches that promise more widespread application are under investigation Citation[9,10].
Another important disease that is characterized by iron overload is hemochromatosis. Hereditary hemochromatosis is caused by mutations in any of several genes whose protein products are involved in the regulation of iron uptake or release into the bloodstream Citation[11]. The extent of disease, the age at which it develops and the symptoms at presentation are variable and largely associated with the specific mutation that has given rise to the disease. For example, mutations in HJV or the gene encoding hepcidin (HAMP) result in juvenile hemochromatosis, which is indicated by early-onset and rapid disease progression. Individuals with mutations in TFR2 typically present with a milder disease characterized by slower progression. The most common form of hemochromatosis is associated with mutations in the HFE gene; however, penetrance is low. In many individuals the HFE mutations only predispose to disease; other factors are usually required to initiate development of the disorder Citation[11]. Mutations in FPN that render the protein unresponsive to HAMP can also result in iron overload Citation[12]. In all instances of hemochromatosis, the pathogenic accumulation of iron in organs generates reactive oxygen species-mediated damage resulting in serious complications, including cirrhosis, joint disease, cardiac failure and hepatocellular carcinoma. Current treatments for hemochromatosis consist of phlebotomy and iron chelation Citation[11].
The delineation of the role of HAMP in FPN regulation has raised the hope that diseases of iron overload can be treated by more specific approaches than those currently available. In the case of β-thalassemia, these hopes have been encouraged by the results of recent studies. Specifically, a β-thalassemia intermedia (th3/+) mouse model has been used to examine the effects of transgenic Hamp expression on iron overload. This study indicates that expression of moderate levels of transgenic Hamp increased hemoglobin levels while simultaneously decreasing organ iron content. Transgenic Hamp expression in these animals also reduced splenomegaly and increased erythropoiesis, as evidenced by decreased numbers of erythroid progenitor cells in the spleen and an enhanced red blood cell lifespan. Of note, expression of high levels of Hamp resulted in pronounced anemia and an increased splenic iron concentration indicative of impaired iron recycling by macrophages Citation[9]. Similarly, experiments examining the effects of transferrin injection in another mouse model of β-thalassemia intermedia (th1/th1) indicate that exogenous transferrin increased Hamp expression and resulted in increased hemoglobin production, improved erythropoiesis, enhanced red blood cell survival and decreased splenomegaly Citation[13]. These data suggest that treatment with a HAMP agonist, albeit at a carefully defined dose, has the potential to ameliorate several aspects of β-thalassemia intermedia due to the specific reduction of iron overload and splenomegaly.
Hereditary hemochromatosis is also an excellent candidate for treatment with a HAMP agonist, as evidenced by the fact that HAMP deficiency almost universally underlies the pathogenesis of this disease. There are several sources of experimental support for this hypothesis. In one investigation, intraperitoneal injection of Hamp resulted in decreased plasma iron levels in a mouse model of hemochromatosis (Hfe-/-) Citation[14]. In another study, transgenic Hamp expression in adult Hfe-/- mice with established iron overload was sufficient to cause a redistribution of iron in the liver and spleen from parenchymal cells to Kupffer cells and splenic macrophages, respectively Citation[15]. When the transgenic expression of Hamp in Hfe-/- mice begins in early fetal development, it prevents the iron accumulation that normally accompanies this disorder Citation[16]. Additional evidence, albeit indirect, is obtained from a study investigating the treatment of Hfe-/- mice with high doses of exogenous Bmp6. Results indicate that treatment with Bmp6 is sufficient to increase Hamp, decrease both serum iron and tranferrin saturation, and redistribute stored iron to appropriate compartments. The failure to observe a decrease in organ iron content in this study may be attributed to the limited time-frame of the study Citation[17]. These data present promising evidence supporting the potential therapeutic utility of HAMP in treating hemochromatosis.
Although hereditary hemochromatosis and β-thalassemia represent two of the best-suited candidates, several other diseases may benefit from modulation of HAMP expression. For example, the pathophysiology of the anemia of inflammation suggests that this condition would be an ideal candidate for treatment with HAMP antagonists Citation[18]. Similarly, anemia arising from certain cancers, such as multiple myeloma and hepatic adenomas that produce HAMP, would likely benefit from the development of HAMP antagonists Citation[19,20]. Alternatively, inhibitors targeting upstream members of the regulatory cascades that control HAMP may be used to produce the same effect. Regardless, the extraordinary amount of research that has focused on iron metabolism since the discovery of HAMP has resulted in novel strategies directed at the underlying pathology of diseases characterized by iron overload and/or anemia. Multiple lines of evidence from laboratories around the world have converged on HAMP as a rational therapeutic agent for treatment of hemochromatosis and β-thalassemia. Testing this approach provides an exciting opportunity to improve the current treatment strategies for these diseases.
Acknowledgements
We thank Robert W Grady, Lori M Bystrom and Laura Breda for careful review of the manuscript.
Financial & competing interests disclosure
This work was supported in part by NIH grants 1R01DK090554 (Stefano Rivella) and the Cooley’s Anemia Foundation (Sara Gardenghi). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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