Schematic model of the proposed mechanism of hepcidin regulation. Representation of the proposed pathways of Id1 control: the first Bmp6-dependent and the second EPO-dependent (see Discussion for details). The thickness of the arrows is proportional to the intensity of the signal. WT mice: low activation of the Bmp-Smad pathway causes basal transcription of Hamp (higher in females, because of their more abundant iron stores) and of the other targets (Id1, Smad7, and Atoh8). The latters are modulated also by the erythroid regulator through a still unknown pathway. Id1 induces transcription of Tmprss6, which by cleaving Hjv, inhibits Hamp transcription, activating a negative feedback loop.47 Hbbth3/+ (th3/+) mice: in males there is a significant iron overload which increases Bmp6 production and a concurrent strong ineffective erythropoiesis which up-regulates Id1 and consequently Tmprss6 transcription. The balance between the positive (Bmp6) and the negative (Tmprss6) regulators of the Bmp-Smad pathway, leaves Hamp mRNA levels unchanged compared with WT mice. In the less anemic females the erythropoietic effect is lower and probably irrelevant on the Id1 transcription, overcome by the strong up-regulation of Bmp6 and resulting in Hamp levels similar to WT mice. Tmprss6−/−Hbbth3/+mice: the loss of Tmprss6 increases the activation of the Bmp-Smad pathway. The effect is more pronounced in females, because of their higher Bmp6 levels. In the absence of Tmprss6, the erythroid factor is ineffective and Hamp transcription remains up-regulated.
