The discovery of hepcidin clarified the basic mechanism of the control of 
systemic iron homeostasis. Hepcidin is mainly produced by the liver as a 
propeptide and processed by furin into the mature active peptide. Hepcidin binds 
ferroportin, the only cellular iron exporter, causing the internalization and 
degradation of both. Thus hepcidin blocks iron export from the key cells for 
dietary iron absorption (enterocytes), recycling of hemoglobin iron (the 
macrophages) and the release of storage iron from hepatocytes, resulting in the 
reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major 
regulator of hepcidin expression that responds to iron status. Also inflammation 
stimulates hepcidin via the IL6/STAT3 pathway with a support of an active 
BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is 
inadequately elevated and reduces iron availability in the body, resulting in 
anemia. These conditions occur in the genetic iron refractory iron deficiency 
anemia and the common anemia of chronic disease (ACD) or anemia of inflammation. 
Currently, there is no definite treatment for ACD. Erythropoiesis-stimulating 
agents and intravenous iron have been proposed in some cases but they are 
scarcely effective and may have adverse effects. Alternative approaches aimed to 
a pharmacological control of hepcidin expression have been attempted, targeting 
different regulatory steps. They include hepcidin sequestering agents 
(antibodies, anticalins, and aptamers), inhibitors of BMP/SMAD or of IL6/STAT3 
pathway or of hepcidin transduction (siRNA/shRNA) or ferroportin stabilizers. In 
this review we summarized the biochemical interactions of the proteins involved 
in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat 
models with high hepcidin levels currently available and finally the progresses 
in the development of hepcidin antagonists, with particular attention to the 
role of heparins and heparin sulfate proteoglycans in hepcidin expression and 
modulation of the BMP6/SMAD pathway.