Albertine Donker

Chapter 1 16 On the molecular level, multiple signaling pathways, sensing body iron, inflammation and erythropoietic drive, control hepcidin synthesis. The bone morphogenetic protein (BMP)/ sons of mothers against decapentaplegic (SMAD) is the main signaling pathway to regulate the transcription of the HAMP gene encoding hepcidin, in particular inside the hepatocyte ( Figure 2 ). 11 Although several BMP’s are expressed in the liver (BMP2, BMP4, BMP5, BMP6. BMP9) only BMP2 and BMP6 have been demonstrated to been involved in hepcidin activation so far. 26 Both BMP2 and BMP6 are produced by liver sinusoidal endothelial cells (LSEC). 27 The iron-induced signaling cascade inside the hepatocyte is initiated following an increase of circulating transferrin-bound iron (TBI) and the endothelial secretion of BMP6. The endothelial production of BMP2 is less iron dependent than the production of BMP6; BMP2 is the prevalent ligand that maintains basal hepcidin transcription while BMP6 is strongly up- regulated in case of (imminent) tissue IO. 27,28 At the hepatocyte membrane level, BMP6 and BMP2 bind to the BMP receptor complex, including the BMP type 1 receptors, activin receptor-like kinase 2 (ALK2) or activin receptor-like kinase 3 (ALK3), and the BMP type 2 receptors, BMP receptor 2 (BMPR2) or activin receptor type 2A (ACVR2A). 29 This binding triggers intra-cellular phosphorylation of SMAD1, SMAD5 and SMAD8 and the formation of heteromeric complexes with SMAD4. Subsequently, the SMAD complex is translocated to the nucleus of the hepatocyte where it activates hepcidin transcription upon binding to BMP-responsive elements (BMP-RE’s). 27,28 Efficient iron signaling via the BMP/ SMAD pathway to the HAMP gene requires the BMP co-receptor hemojuvelin (HJV), the hemochromatosis protein HFE and the transferrin receptor 2 (TfR2). 27 Increased levels of TBI also positively regulate hepcidin synthesis to prevent IO. High circulating levels of TBI result in a shift of binding of HFE from transferrin receptor 1 (TfR1) to TfR2, which can then activate the BMP-SMAD pathway through interactions with HJV and ALK3. 30,31 Pathologic variants of HFE and TfR2 cause inappropriately decreased serum hepcidin levels resulting in IO. 25,32 In case of inflammation the cytokine interleukin 6 (IL6) and activin B induce hepcidin transcription via the janus kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3) signaling pathway and the BMP-SMAD pathway, respectively. The binding of IL6 triggers dimerization of IL6 receptors (IL6R’s) on the membrane of the hepatocyte, with subsequent intracellular phosphorylation of STAT3. This phosphorylated complex is translocated to the nucleus where