Iron homeostasis: casting new roles

In this issue of Blood, Folgueras and colleagues show that the transmembrane serine protease matriptase-2 plays an essential role in the regulation of systemic iron homeostasis.

The type II transmembrane serine proteases (TTSPs) are a family of membrane-associated proteases sharing several structural motifs, including a short cytoplasmic amino-terminal tail, a single-pass transmembrane domain, a central region containing modular domains that may participate in protein-protein interactions, and a carboxy-terminal catalytic domain. TTSPs differ in their patterns of tissue expression, suggesting that the different family members may have distinct physiological roles.¹  Matriptase-2, encoded by the gene Tmprss6, is a TTSP family member primarily expressed in the liver.^2,3  Although in vitro studies have shown that matriptase-2 is capable of degrading several components of the extracellular matrix,²  the in vivo role of matriptase-2 remained to be elucidated.

In this issue of Blood, Folgueras et al explore the physiological roles of matriptase-2 by generating mutant mice deficient in this TTSP through gene targeting methods. Mice lacking matriptase-2 (Tmprss6^−/− mice) displayed iron deficiency anemia and hair loss. Levels of messenger RNA encoding the iron regulatory hormone hepcidin were increased in the livers of Tmprss6^−/− mice compared with wild type controls, providing insight into the pathophysiology underlying the iron deficiency anemia. Hepcidin, a small peptide synthesized by the liver, acts to decrease absorption of dietary iron into the bloodstream by causing the internalization and degradation of ferroportin, an iron exporter expressed at the basolateral surface on duodenal enterocytes.⁴  Consistent with elevated circulating levels of hepcidin, ferroportin expression was markedly reduced in Tmprss6^−/− duodenal enterocytes; these cells were also shown to retain iron, consistent with a defect in intestinal iron absorption. Accordingly, subcutaneous iron dextran administration rescued the hematological defects in Tmprss6^−/− mice. Iron dextran therapy also led to complete recovery of body hair, suggesting that the hair loss phenotype was a direct consequence of iron deficiency. The findings of Folgueras et al complement the recently reported phenotypic characterization of a chemically induced Tmprss6 mouse mutant, in which impaired absorption of orally administered radiolabeled iron provided direct functional evidence for an intestinal iron uptake defect.⁵ 

The iron regulatory function of matriptase-2 appears to be conserved between humans and mice, as mutations in the human gene encoding matriptase-2 (TMPRSS6) have been shown to cause an autosomal recessive form of iron deficiency anemia that is refractory to oral iron therapy.^6-8  The inappropriately elevated hepcidin levels observed in Tmprss6^−/− mice, as well as in humans who harbor TMPRSS6 mutations, suggest that matriptase-2 may normally act to down-regulate hepcidin expression at the transcriptional level as a means to maintain systemic iron homeostasis. However, the mechanism by which matriptase-2 regulates hepcidin expression remains to be clarified. How is systemic iron status conveyed to matriptase-2? What is the proteolytic cleavage target (or targets) of matriptase-2? Does matriptase-2 function by modulating the activity of a known hepcidin stimulatory factor (such as bone morphogenetic proteins), a known repressive factor (such as hypoxia inducible factor 1α), or a yet undiscovered regulatory factor?⁴  Does matriptase-2 exert its iron regulatory effect through a proteolytic event that occurs at the hepatocyte surface? Does the short cytoplasmic tail of matriptase-2 mediate intracellular signaling events that ultimately modulate hepcidin expression?

Although many questions regarding the biology of matriptase-2 remain, the newly identified role of matriptase-2 in iron homeostasis nevertheless suggests that modulation of the activity of this TTSP may hold promise for the treatment of clinical disorders of iron metabolism associated with dysregulated hepcidin expression. Inappropriately increased gastrointestinal iron absorption associated with abnormally low hepcidin levels underlies iron overload in several forms of hereditary hemochromatosis and iron-loading anemias. Thus, pharmacological inhibition of matriptase-2 function might be employed to increase hepcidin levels in patients with these disorders. Likewise, in the anemia of inflammation, a condition in which hepcidin levels are inappropriately elevated, administration of matriptase-2 agonists or perhaps the endogenous substrate of matriptase-2 might be employed to decrease hepcidin levels.