An ancient disorder under iron control

Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to iron accumulation and organ damage and was first described 150 years ago (1). The most commonly used test to diagnose HH is based on determining the level of transferrin saturation and ferritin concentration in serum samples and periodic phlebotomy (blood removal) is an important step in the treatment of HH. Recent advances in molecular biology have identified the gene responsible, called HFE, that accounts for the majority of HH cases. HFE associated hemochromatosis is most common in individuals of northern European ancestry (1 in 300 Caucasians), but it also occurs in African and Asian populations. However, the function of HFE is still unclear. Recent success in our understanding of the underlying mechanisms regulating iron homeostasis came from the recent identification of genes causing two juvenile forms of HH, hemojuvelin (HJV) and hepcidin (HAMP) (2). Mutations in these genes, as mutations in other genes causing HH, reduce the expression of hepcidin by liver hepatocytes to varying degrees with the most profound changes and the greatest iron overload in juvenile forms of HH (Table 1). Hepcidin is a central regulator of iron metabolism and controls the iron export from iron-storing macrophages and intestinal enterocytes into the serum (Fig. 1). This function of hepcidin is enabled by its binding to ferroportin and subsequent ferroportin degradation. This explains why mutations lowering hepcidic expression lead to iron overload with very high serum ferritin levels and elevated transferrin saturation in HH. Mutations in hemojuvelin, a member of the repulsive guidance molecule (RGM) family, act in a similar manner. Hemojuvelin controls the expression of hecidin in hepatocytes by signaling through the Smad signaling pathway together with its co-receptor for bone morphogenic proteins (BMPs), a member of the TGF-β superfamily. However, despite the fact that BMP ligands regulate hepcidin expression in vitro, it was unknown until recently how iron modulates BMP signaling in vivo and which BMPs regulate hepcidin expression and iron metabolism in vivo. Much progress addressing these questions has been achieved by two independent studies demonstrating that Bmp6 is a key endogenous regulator of hepcidin expression and iron metabolism (3, 4). Both studies demonstrate that Bmp6 knock-out mice develop hallmarks of HH and resemble mice with targeted disruption of HJV, Smad4 and HAMP showing massive iron accumulation in hepatocytes and reduced iron in spleenic macrophages. Moreover, the iron content in serum of Bmp6 knock-out mice is profoundly increased and transferrin saturation approaches close to 100%. Meynard et al. (4) demonstrate that this phenotype is accompanied by a reduction in Bmp6dependent Smad signaling, a reduction in hepatic mRNA expression of Hamp and increased expression of ferroportin mRNA in the duodenum. In addition, Meynard et al. demonstrate that antagonizing Bmp6 signaling in vitro and in vivo with either a soluble form of hemojuvelin (s-HJV-Fc) or anti-Bmp6 antibodies leads to reduced expression of HAMP mRNA and increased liver iron content. In contrast, Bmp6 administration in mice increases HAMP mRNA expression and reduces serum iron and transferrin saturation. This data together with the observed direct interaction of Bmp6 and s-HJV-Fc provide strong evidence that Bmp6 is a ligand for hemojuvelin and that Bmp6 is a regulator of hepcidin expression and iron metabolism in vivo. Of interest, Bmp6 itself is regulated by iron, since Bmp6 and HAMP mRNA expression is induced in mice fed with a high iron diet (5). This