Albertine Donker

General Introduction 17 1 it activates hepcidin transcription upon binding to a STAT-responsive element (STAT-RE) in the HAMP promoter. 27,28 On the other hand, suppression of hepcidin transcription is crucial in conditions of ID. The main hepcidin inhibitor responsible for this down-regulation is the transmembrane serine protease 6 (matriptase 2, (MT2), encoded by TMPRSS6 ), mainly expressed in hepatocytes. 27,33-36 Defects in TMPRSS6 have provided insights into this mechanism and the crucial role of MT2 in sensing ID and consequent blocking of the hepcidin transcription. Patients with dysfunctional MT2 due to pathologic TMPRSS6 variants have inappropriately elevated hepcidin levels relative to circulating iron, resulting in IDA that is in general refractory to oral iron supplementation and only partially responsive to parenteral iron administration. 37,38 This condition, called Iron Refractory Iron Deficiency Anemia (IRIDA) is a topic of this thesis and addressed in Chapter 3, 4, 5 and 8 . Other proteins that have been proposed to mediate hepcidin suppression via the BMP/SMAD signaling pathway are erythroferrone (ERFE), twisted gastrulation (TWSG1) and growth differentiation factor 15 (GDF15). 11,39-41 Mice studies suggest that ERFE suppresses hepcidin transcriptions in both conditions of blood loss with subsequent appropriate increased erythropoiesis and anemias accompanied by iron loading due to ineffective erythropoiesis, whereas GDF15 and TWSG1 seem to play a role only in the last mentioned group. Other erythroid regulators of the hepcidin transcription pathway may exist but still have to be identified. 39 Iron-regulatory proteins control cellular iron metabolism by binding to Iron- responsive elements in regulated messenger RNA’s Coordination of iron uptake, utilization and storage is also required on the cellular level in order to assure the availability of appropriate supplies and to prevent toxicity due to iron surplus. In contrast to systemic iron metabolism, cellular iron traffic also involves regulated cellular iron excretion. 11,15