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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.
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PMID:Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). 1840 18

Hepcidin, the systemic regulator of iron homeostasis is activated by proteins responsible for hereditary hemochromatosis, bone morphogenetic proteins (BMPs), and inflammatory cytokines. Three recent publications now identify a novel hepcidin suppressor, the transmembrane serine protease TMPRSS6 (also known as matriptase-2), which is required to sense iron deficiency.
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PMID:Fine tuning of hepcidin expression by positive and negative regulators. 1859 Jun 84

The liver peptide hepcidin regulates body iron, is upregulated in iron overload and inflammation, and is downregulated in iron deficiency/hypoxia. The transmembrane serine protease matriptase-2 (TMPRSS6) inhibits the hepcidin response and its mutational inactivation causes iron-deficient anemia in mice and humans. Here we confirm the inhibitory effect of matriptase-2 on hepcidin promoter; we show that matriptase-2 lacking the serine protease domain, identified in the anemic Mask mouse (matriptase-2(MASK)), is fully inactive and that mutant R774C found in patients with genetic iron deficiency has decreased inhibitory activity. Matriptase-2 cleaves hemojuvelin (HJV), a regulator of hepcidin, on plasma membrane; matriptase-2(MASK) shows no cleavage activity and the human mutant only partial cleavage capacity. Matriptase-2 interacts with HJV through the ectodomain since the interaction is conserved in matriptase-2(MASK). The expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and its interaction with HJV.
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PMID:The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. 1897 66

Matriptase-2 is a recently identified membrane-bound, cell-surface serine protease expressed primarily in liver. Mutations in matriptase-2 in mice and humans cause iron-deficiency anemia that responds poorly to iron therapy. The poor response results from an inability to decrease hepcidin production during iron deficiency. Cell culture studies reveal that matriptase-2 inhibits hepcidin induction by cleaving membrane hemojuvelin, a potent activator of hepcidin transcription. As a novel suppressor of hepcidin expression, matriptase-2 emerges as a possible candidate for therapeutic interventions aimed at treating disorders of iron metabolism.
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PMID:Into the matrix: regulation of the iron regulatory hormone hepcidin by matriptase-2. 1938 32

Iron deficiency anemia is a common complication in end-stage renal disease (ESRD) and impairs the therapeutic efficacy of recombinant erythropoietin. Oral or parental iron supplements usually are effective in treating iron deficiency anemia. Some patients, however, respond poorly to iron supplements and are diagnosed as having iron-refractory iron deficiency anemia. The condition exacerbates ESRD but its underlying mechanism was unclear. Hepcidin is a central player in iron homeostasis. It downregulates the iron exporter ferroportin, thereby inhibiting iron absorption, release, and recycling. In ESRD, plasma hepcidin levels are elevated, which contributes to iron deficiency in patients. Matriptase-2, a liver transmembrane serine protease, has been found to have a major role in controlling hepcidin gene expression. In mice, defects in the Tmprss6 gene encoding matriptase-2 result in high hepcidin expression and cause severe microcytic anemia. Similarly, mutations in the human TMPRSS6 gene have been identified in patients with iron-refractory iron deficiency. Thus, matriptase-2 is critical for iron homeostasis and may have an important role in ESRD.
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PMID:Iron-refractory iron deficiency anemia: new molecular mechanisms. 1977 21

Iron, an essential element for life, is regulated primarily at the level of uptake, storage, and transport in order to maintain sufficient availability for normal physiology. The key protein in iron homeostasis is a 25-amino-acid peptide, hepcidin, which modulates the amount of iron in the circulation by binding and promoting the degradation of the iron exporter ferroportin. Given the central importance of hepcidin, recent studies have focused on how iron is sensed and how the iron signal is transmitted to hepcidin. Mutations in a type II serine protease, matriptase-2/TMPRSS6, were recently identified to be associated with severe iron deficiency caused by inappropriately high levels of hepcidin expression. A key biologically relevant substrate for the proteolytic activity of matriptase-2/TMPRSS6 was found to be hemojuvelin, a cell surface protein that regulates hepcidin expression through a BMP/SMAD pathway. In this review, we discuss the putative role of matriptase-2/TMPRSS6 in iron homeostasis.
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PMID:Role of matriptase-2 (TMPRSS6) in iron metabolism. 1990 45

Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6(-/-) mice (characterized by increased hepcidin levels and anemia) and Bmp6(-/-) mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6(-/-) mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.
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PMID:Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6. 2094 Apr 20

The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe(-/-) mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/Smad target genes. In contrast, neither genetic loss of Hfe nor hepatic Hfe overexpression modulated the hepcidin elevation and systemic iron deficiency of Tmprss6(-/-) mice. These results indicate that genetic loss of Tmprss6 increases Bmp/Smad signaling in an Hfe-independent manner that can restore Bmp/Smad signaling in Hfe(-/-) mice. Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder.
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PMID:Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. 2135 94

The iron hormone hepcidin is inhibited by matriptase-2 (MT2), a liver serine protease encoded by the TMPRSS6 gene. Cleaving the bone morphogenetic protein (BMP) coreceptor hemojuvelin (HJV), MT2 impairs the BMP/son of mothers against decapentaplegic homologs (SMAD) signaling pathway, down-regulates hepcidin, and facilitates iron absorption. TMPRSS6 inactivation causes iron-deficiency anemia refractory to iron administration both in humans and mice. Genome-wide association studies have shown that the SNP rs855791, which causes the MT2 V736A amino acid substitution, is associated with variations of serum iron, transferrin saturation, hemoglobin, and erythrocyte traits. In the present study, we show that, in vitro, MT2 736(A) inhibits hepcidin more efficiently than 736(V). Moreover, in a genotyped population, after exclusion of samples with iron deficiency and inflammation, hepcidin, hepcidin/transferrin saturation, and hepcidin/ferritin ratios were significantly lower and iron parameters were consistently higher in homozygotes 736(A) than in 736(V). Our results indicate that rs855791 is a TMPRSS6 functional variant and strengthen the idea that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis.
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PMID:TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. 2187 47

Cell surface proteins Hfe, Tfr2, hemojuvelin and Tmprss6 play key roles in iron homeostasis. Hfe and Tfr2 induce transcription of hepcidin, a small peptide that promotes the degradation of the iron transporter ferroportin. Hemojuvelin, a co-receptor for bone morphogenic proteins, induces hepcidin transcription through a Smad signaling pathway. Tmprss6 (also known as matriptase-2), a membrane serine protease that has been found to bind and degrade hemojuvelin in vitro, is a potent suppressor of hepcidin expression. In order to examine if Hfe and Tfr2 are substrates for Tmprss6, we generated mice lacking functional Hfe or Tfr2 and Tmprss6. We found that double mutant mice lacking functional Hfe or Tfr2 and Tmprss6 exhibited a severe iron deficiency microcytic anemia phenotype mimicking the phenotype of single mutant mice lacking functional Tmprss6 (Tmprss6msk/msk mutant) demonstrating that Hfe and Tfr2 are not substrates for Tmprss6. Nevertheless, the phenotype of the mice lacking Hfe or Tfr2 and Tmprss6 differed from Tmprss6 deficient mice alone, in that the double mutant mice exhibited much greater erythropoiesis. Hfe and Tfr2 have been shown to play important roles in the erythron, independent of their role in regulating liver hepcidin transcription. We demonstrate that lack of functional Tfr2 and Hfe allows for increased erythropoiesis even in the presence of high hepcidin expression, but the high levels of hepcidin levels significantly limit the availability of iron to the erythron, resulting in ineffective erythropoiesis. Furthermore, repression of hepcidin expression by hypoxia was unaffected by the loss of functional Hfe, Tfr2 and Tmprss6.
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PMID:Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6. 2224 35


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