Decreased hepcidin mRNA expression in thalassemic mice

Adamsky, Konstantin; Weizer, Orly; Amariglio, Ninette; Breda, Laura; Harmelin, Alon; Rivella, Stefano; Rachmilewitz, Eliezer A.; Rechavi, Gideon

doi:10.1046/j.1365-2141.2003.04734.x

Cited by 95 publications

(80 citation statements)

References 7 publications

(6 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hepcidin is only regulated at the transcriptional level, and expression is inhibited by anemia, hypoxia (19), and ineffective erythropoiesis (20), and stimulated by iron loading and inflammation. Multiple lines of inquiry have demonstrated that members of the TGF-␤ superfamily, including BMP receptors, associated BMP ligands, and the cytoplasmic SMAD transcription factors (homologs of the Caenorhabditis elegans protein SMA and the Drosophila protein mothers against decapentaplegic (MAD)) play a central role in transcriptionally regulating hepcidin expression (Fig.…”

Section: Regulation Of Hepcidin Through the Bone Morphogenetic Proteimentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

137

105

View full text Add to dashboard Cite

Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

show abstract

Section: Regulation Of Hepcidin Through the Bone Morphogenetic Proteimentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

137

105

View full text Add to dashboard Cite

show abstract

“…8,9 In contrast to human patients who have dramatically reduced hepcidin production even in adulthood, [2][3][4][5] in the Th3/1 model, liver hepcidin mRNA expression is only low in young mice compared with wild-type (WT) mice of the same age; in adult Th3/1 mice, hepcidin expression becomes similar to that of WT mice. 10,11 However, even in adult Th3/1 mice, hepcidin levels are inappropriately low, considering their iron overload, consistent with the concept that inadequate levels of hepcidin cause the iron overload in thalassemic mice.…”

Section: Introductionmentioning

confidence: 99%

Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia

Kautz¹,

Jung²,

Du³

et al. 2015

Blood

260

262

View full text Add to dashboard Cite

Inherited anemias with ineffective erythropoiesis, such as β-thalassemia, manifest inappropriately low hepcidin production and consequent excessive absorption of dietary iron, leading to iron overload. Erythroferrone (ERFE) is an erythroid regulator of hepcidin synthesis and iron homeostasis. Erfe expression was highly increased in the marrow and spleen of HbbTh3/+ mice (Th3/+), a mouse model of thalassemia intermedia. Ablation of Erfe in Th3/+ mice restored normal levels of circulating hepcidin at 6 weeks of age, suggesting ERFE could be a factor suppressing hepcidin production in β-thalassemia. We examined the expression of Erfe and the consequences of its ablation in thalassemic mice from 3 to 12 weeks of age. The loss of ERFE in thalassemic mice led to full restoration of hepcidin mRNA expression at 3 and 6 weeks of age, and significant reduction in liver and spleen iron content at 6 and 12 weeks of age. Ablation of Erfe slightly ameliorated ineffective erythropoiesis, as indicated by reduced spleen index, red cell distribution width, and mean corpuscular volume, but did not improve the anemia. Thus, ERFE mediates hepcidin suppression and contributes to iron overload in a mouse model of β-thalassemia.

show abstract

“…In fact, Hbb th3/+ mice were the first to show a correlation between relative low hepcidin mRNA levels in the liver and iron overload in this disorder. 127,128 Altogether, these new notions, together with the use of the b-thalassemic mouse models, have been utilized to identify new drugs or strategies that are currently under development or in clinical trial; these will be described in the next sections. Another class of compounds that might also benefit b-thalassemia are fetal hemoglobin inducers; these will not be discussed in this manuscript but were recently summarized in several excellent reviews.…”

Section: Th3/+mentioning

confidence: 99%

“…[142][143][144] In addition, in Hbb th1/th1 mice, it has been shown that oxidative stress, through the Gdf11 ligand (Figure 3), also decreases apoptosis through overactivation of the Fas-Fas ligand pathway. 126,127 As mentioned previously, both decreased apoptotic rate and maturation of early erythroid precursors leads to exacerbation of IE, splenomegaly, and increased iron absorption. 117,128,129 Furthermore, these compounds also target the aberrant metabolism that leads to premature osteoporosis in this disorder, improving bone structure in these mice.…”

mentioning

confidence: 99%

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

2015

View full text Add to dashboard Cite

b-thalassemias are monogenic disorders characterized by defective synthesis of the b-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the b-globin gene or its regulatory elements have been associated with b-thalassemias. Due to the complexity of the regulation of the b-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of b-globin and abnormal erythropoiesis, as well as current and novel therapies. ABSTRACTThe complex phenotype of b-thalassemias b-thalassemias are monogenic disorders characterized by reduced or no synthesis of the b-globin chain, one of the major components of adult hemoglobin (HbA). Several hundred mutations in the b-globin gene or regulatory elements have been associated with b-thalassemias.

show abstract

Decreased hepcidin mRNA expression in thalassemic mice

Cited by 95 publications

References 7 publications

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

Contact Info

Product

Resources

About