8 In contrast, administration of exogenous Bmp6 to mice increased hepatic Hamp expression and reduced both serum iron and transferrin saturation (TS).2, 9 Liver-specific Smad4 null mice also developed iron overload

and impaired Bmp signaling, suppressing hepcidin production.4 Taken together, these observations strongly support VX-765 mw BMP6 as the key endogenous regulator of hepcidin synthesis and iron metabolism in vivo. Recently, it was shown that inhibitory SMAD7 tempers HAMP expression by blocking the interaction of SMAD1/5/8 with SMAD4.10 TFR2 and HFE are thought to act as iron-sensing molecules to receive signals from circulating holotransferrin to modulate hepatic HAMP expression. TFR2 is a strong candidate as a sensor of serum TS, because it binds holotransferrin and undergoes posttranslational stabilization.11 As TS increases, HFE dissociates from TFR1 and binds to TFR2 to possibly convey the necessary signal downstream to stimulate hepcidin synthesis.12, 13 Some studies support the premise that TFR2 and HFE interact with the BMP6–SMAD pathway, because this signaling pathway is impaired in Tfr2 and/or Hfe null mice9, 14-16 as well as in subjects with HFE-associated HH,17, 18 whereas others report no interaction.5 TFR2 and HFE may also signal independently of

each other, because disruption of both Tfr2 and Hfe in mice causes a more severe iron overload phenotype.16 TFR2 and HFE, however, are likely to modulate SMAD signaling downstream Inhibitor Library price of BMP6 due to their redundancies in BMP6 transcription.7, 14, 15 Holotransferrin, through TFR2 and HFE signaling, may also regulate hepcidin by activating the extracellular signal-regulated kinases 1 and 2 and mitogen-activated protein kinases (ERK1/2–MAPK) pathway16, 19, 20 and interact with the BMP–SMAD pathway.16, 19 The interaction between

BMP–SMAD and ERK–MAPK pathways is not fully understood. The current study by Corradini et al.21 adds to an actively expanding body of work to unravel the complexities of hepcidin regulation by iron. Iron-dependent ADP ribosylation factor regulation of hepcidin appears to involve both liver iron and circulating iron levels.7, 21 The modulation of hepcidin expression by liver iron is likely to be mediated through the BMP6–SMAD signaling pathway, whereas regulation by serum TS is mediated by TFR2 and HFE signaling, although the latter mechanism remains poorly defined. Corradini et al.21 show that, in a setting where there was a sudden surge in circulating iron levels with unaltered liver iron concentration (LIC), hepcidin responded according to the changes in serum TS. Mice administered 2 mg/kg iron (through oral gavage) had increased serum iron and TS levels after 1 hour of iron dosing, which returned to baseline levels by 8-24 hours, whereas LIC was unchanged over 24 hours.