211 Support for this notion also comes from patients with β-thalassemia, who have low serum hepcidin levels despite iron overload.212 Growth differentiation factor 15 (GDF-15) and twisted gastrulation homolog 1 (TWSG1) have been identified as candidate erythrokines, although not erythroblast-specific, that have the potential to suppress hepcidin under conditions of increased

erythropoietic activity.[213], [214] and [215] GDF15 is an iron- and O2-regulated (HIF-independent) member of the TGF-β superfamily, which is secreted from maturing erythroblasts and has been shown to suppress selleck products hepcidin transcription in primary human hepatocytes and hepatoma cells (Fig. 3).[213] and [216] While increased GDF15 serum levels associate with syndromes of ineffective erythropoiesis, for example α- and β-thalassemia, its role in hepcidin regulation under physiologic conditions and in other forms of anemia remains unclear.[213], [215], [217], [218] and [219] Therefore, it was proposed that GDF15 may be a marker of bone marrow stress or erythroblast apoptosis.215 find more Elevated serum GDF15

level have also been found in patients with heart failure,220 which adds complexity to this model. We found that recombinant murine GDF15 suppressed hepcidin in Hep3B cells at a concentration of 750 pg/ml.207 This is in contrast to previous reports where higher doses of GDF15 were needed to achieve hepcidin suppression in human HuH-7 hepatoma cells and in primary hepatocytes, while low dose GDF15 treatment increased hepcidin.213 While demonstrated in mice, studies in humans receiving recombinant EPO have not yet shown a significant inverse relationship between serum hepcidin and GDF15 levels, which may

relate to the EPO doses administered, study size, complexity Parvulin of regulation and species-dependent differences.[207] and [221] In the context of iron-deficiency anemia, Tanno and colleagues found that GDF15 serum levels were not elevated,222 while Lakhal and colleagues reported that patients with low serum iron had elevated GDF15 levels compared to iron-replete controls (mean of 1048 pg/ml vs. 542 pg/ml).216 Similarly, increased serum GDF15 levels were found following DFO treatment, suggesting iron-dependent regulation.216 Furthermore, temporary increases in serum GDF15 levels associated with increased serum EPO following ascent to high altitude.211 In addition to regulating iron metabolism, hypoxia has direct effects on the bone marrow. It promotes erythropoiesis by modulating erythroid progenitor maturation and proliferation.[223] and [224] Hypoxia stimulates EPOR expression and regulates components of the hemoglobin synthesis pathway.[52], [53], [54], [225] and [226] Hypoxia also modulates the interaction of erythroid progenitors with other cell types and thereby regulates stem cell maintenance, lineage differentiation and maturation.