Model of relationship among Hfe, Tmprss6, and the Bmp/Smad signaling pathway in hepcidin regulation. Our data are compatible with a model in which Hfe promotes Bmp/Smad signaling for hepcidin production by inhibiting the activity of Tmprss6 (A). However, we cannot exclude the possibility that Hfe promotes Bmp/Smad signaling by a mechanism that is independent of Tmprss6 but nevertheless cannot achieve a further elevation in Bmp/Smad target gene expression when Tmprss6 is absent. Hfe might, for example, promote Bmp/Smad signaling by Hjv (B) or promote Bmp/Smad signaling at a point functionally downstream of Tmprss6 (C).