Similar results were recently obtained with ubiquitous Hjv−/− mice.34 These results are consistent with the restoration of hepcidin expression HIF inhibitor and normalization of iron parameters upon reintroduction of Hjv to hepatocytes of Hjv−/− mice by an adenoviral system,34 and highlight the importance of the liver in body iron metabolism as a site of both hepcidin production and regulation by Hjv. Our data support the hypothesis that Hjv may constitute part of an “iron sensing complex” (possibly together with HFE, TfR2, and further molecules) that responds to alterations

in transferrin saturation and/or BMP6 levels, and transmits signals for hepcidin transcriptional activation by way of the BMP/SMAD pathway.40, 41 According to this model, Hjv would be expected to operate in a cell-autonomous fashion at the sites of hepcidin production in the liver. Although hepcidin appears to be predominantly expressed in periportal hepatocytes,20, 42 discordant results have been published about the site of hepatic Hjv expression. By measuring lacZ activity in liver sections of Hjv−/− mice where lacZ was introduced from the targeting vector, Niederkofler et al.6 reported a patterned distribution of Hjv around periportal hepatocytes. However, by in situ hybridization of Hjv mRNA and immunohistochemical staining with an Hjv antibody, Lee at al.20 concluded that Hjv is mostly expressed MAPK inhibitor around

the central vein of the liver. Certainly, more work is required to clarify this important issue. Periportal expression of Hjv would support a cell-autonomous activity of this protein on hepcidin regulation. Nevertheless, if the majority of hepatic Hjv is concentrated around perivenous areas, an activity of Hjv in trans would be conceivable. We also show here that mice with specific ablation of Hjv in skeletal muscles and cardiomyocytes do not develop iron overload and do not exhibit any apparent phenotypic abnormalities. This finding is intriguing, considering that skeletal muscles express substantially higher levels of Hjv compared to the liver,5, 13 and suggests that muscle see more Hjv is not involved

in the regulation of systemic iron homeostasis, at least under standard laboratory conditions. The absence of cardiac iron overload in muscle-specific Hjv−/− mice appears to exclude the possibility for a local iron regulatory function of this protein Nevertheless, it will be interesting to evaluate iron metabolism in Hfe2f/f:MCK-Cre mice subjected to stress, such as strenuous physical exercise or hypoxia. Moreover, it will be important to examine whether these mice exhibit any possible phenotype in muscles, unrelated to iron metabolism. In light of the high abundance of Hjv in skeletal muscles and the capacity of differentiating muscle cells to release sHjv,15, 17 it is reasonable to speculate that circulating sHjv may primarily derive from muscle tissue.