Novel tools for the evaluation of iron metabolism.

Iron disorders, including various anemias and iron overload conditions, are common and affect millions of people worldwide. Advances in iron biology over the last decade have prompted a fundamental revision of our understanding of iron homeostasis, and opened the door to a new era of diagnostic and therapeutic developments for iron disorders. During normal homeostasis, iron is conserved. On a daily basis, less than 0.1% of total body iron is lost by shedding of various cells and about the same amount is absorbed from the diet. The bone marrow is the main consumer of circulating iron, which is used for the synthesis of hemoglobin for new red blood cells. Erythrocyte hemoglobin contains most (about two-thirds) of the total body iron. As red blood cells complete their life-span of about 120 days, their iron is recycled by specialized macrophages, and made available for the synthesis of new red blood cells. Restricting iron availability to the bone marrow, as occurs in iron deficiency or in various inflammatory disorders, limits hemoglobin synthesis and results in the development of anemia. At the other extreme, excessive iron absorption or iron loading by multiple blood transfusions leads to iron overload (primarily of the liver, heart and endocrine glands) which can cause organ toxicity due to iron’s ability to catalyze generation of highly reactive oxygen species. Iron absorption and recycling, and thus the availability of iron for hemoglobin synthesis are regulated by the peptide hormone hepcidin. Hepcidin acts by controlling the number of iron channels through which cellular iron is delivered into plasma. In turn, hepcidin concentration is regulated by a variety of influences. Iron loading increases hepcidin production (to block further iron absorption and maintain homeostasis), and so does inflammation (to decrease extracellular iron concentration and its accessibility to microorganisms). On the other hand, iron deficiency and increased erythropoietic activity suppress hepcidin (to increase iron absorption and the release of recycled iron). As would be expected, dysregulation of hepcidin production, whether genetic or acquired, causes iron disorders: a lack of hepcidin leads to iron overload, whereas its excess leads to iron restriction and anemia. Considering hepcidin responsiveness to iron, erythropoiesis and inflammation, as well as its causative role in the pathogenesis of different iron disorders, hepcidin assays may become a useful clinical test for the diagnosis or the monitoring of treatment in various diseases (Table 1). In this issue of the journal, Brasse-Lagnel et al. present a new tool in the arsenal of tests for the evaluation of iron metabolism. They describe the development and validation of the first enzyme-linked immunosorbent assay (ELISA) for soluble hemojuvelin in human serum. Hemojuvelin is an important regulator of hepcidin production. Mutations in hemojuvelin lead to severe hepcidin deficiency and juvenile hemochromatosis, a particularly severe form of genetic iron overload. Hemojuvelin, which is a glycophosphatidylinositol-linked membrane protein, is a member of the repulsive guidance molecule family. Like other members of this family, it is a co-receptor for bone morphogenetic proteins (BMP) and potentiates BMP pathway signaling. The BMP signaling cascade is initiated by BMP binding to a complex composed of two type I and two type II BMP receptors, and hemojuvelin appears to increase the utilization of specific combinations of type I and type II receptors. Upon ligand binding, BMP-type II receptor phosphorylates BMP-type I receptor, and the activated complex phosphorylates receptor-activated Smad proteins. R-Smad proteins form heteromeric complexes with the common mediator Smad4 and translocate to the nucleus to activate the transcription of target genes (e.g. hepcidin) (Figure 1). Hemojuvelin is highly expressed in skeletal muscle and the liver. The biological role of this protein in the muscle is unclear, but in the liver, hemojuvelin appears to be an essential component of the mechanism by which iron regulates hepcidin expression. However, the specifics of hemojuvelin involvement in the sensing of extracellular