Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice

Nai, Antonella; Pagani, Alessia; Silvestri, Laura; Camaschella, Clara

doi:10.1182/blood-2010-04-278655

Cited by 24 publications

(32 citation statements)

References 10 publications

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“…[18][19][20][21][22][23][24] We and others have shown that Tmprss6 haploinsufficient mice have an increased susceptibility to iron deficiency. 9,25 Altogether these results suggest that TMPRSS6 gene dosage may modify erythropoiesis and influence HAMP expression.…”

Section: Introductionmentioning

confidence: 78%

Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

Nai

Pagani

Mandelli

et al. 2012

Blood

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Inappropriately low expression of the key iron regulator hepcidin (HAMP) causes iron overload in untransfused patients affected by ␤-thalassemia intermedia and Hamp modulation provides improvement of the thalassemic phenotype of the Hbb th3/؉ mouse. HAMP expression is activated by iron through the bone morphogenetic protein (BMP)-son of mothers against decapentaplegic signaling pathway and inhibited by ineffective erythropoiesis through an unknown "erythroid regulator." The BMP pathway is inactivated by the serine protease TMPRSS6 that cleaves the BMP coreceptor hemojuvelin. Here, we show that homozygous loss of Tmprss6 in Hbb th3/؉ mice improves anemia and reduces ineffective erythropoiesis, splenomegaly, and iron loading. All these effects are mediated by Hamp up-regulation, which inhibits iron absorption and recycling. Because Hbb th3/؉ mice lacking Tmprss6 show residual ineffective erythropoiesis, our results indicate that Tmprss6 is essential for Hamp inhibition by the erythroid regulator. We also obtained partial correction of the phenotype in Tmprss6 haploinsufficient Hbb th3/؉ male but not female mice and showed that the observed sex difference reflects an unequal balance between iron and erythropoiesis-mediated Hamp regulation. Our study indicates that preventing iron overload improves ␤-thalassemia and strengthens the essential role of Tmprss6 for Hamp suppression, providing a proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in this condition. IntroductionThe liver antimicrobial peptide hepcidin (HAMP) is the central regulator of systemic iron homeostasis. HAMP controls the surface expression of the iron exporter ferroportin on duodenal enterocytes and macrophages, modulating iron absorption and recycling. HAMP is activated by the bone morphogenetic proteins (BMP)-son of mothers against decapentaplegic (SMAD) signaling pathway, in response to increased body iron and by the IL-6-signal transducer and activator of transcription (STAT)3 pathway in inflammation. 1 The glycosylphosphatidylinositol (GPI)-anchored protein hemojuvelin (HJV) is a BMP coreceptor and homozygous mutations of HAMP or HJV cause juvenile hemochromatosis in humans 2,3 and severe iron overload in mice. 4,5 The BMP pathway is inhibited by matriptase-2 (MT-2), a type II transmembrane serine protease encoded by the transmembrane proteaSe serine 6 (TMPRSS6) gene and mainly expressed in the liver. 6,7 MT-2, by cleaving HJV from the hepatocyte surface, attenuates the BMP-SMAD signaling and down-regulates HAMP expression. 8 Mice deficient for both Tmprss6 and Hjv show markedly decreased Hamp mRNA levels and systemic iron overload, as do Hjv deficient mice, 9 in agreement with Hjv being the serine protease substrate.TMPRSS6 plays an essential role for erythropoiesis: homozygous inactivation of the Tmprss6 gene leads to excessive Hamp production, impaired dietary iron absorption and microcytic anemia in mice, 10,11 and iron-refractory iron deficiency anemia (IRIDA) in humans. [12][13][14][15][16][17] The importan...

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Section: Introductionmentioning

confidence: 78%

Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

Nai

Pagani

Mandelli

et al. 2012

Blood

Self Cite

144

132

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…[22][23][24][25][26][27] By studying Tmprss6 haploinsufficient mice 28 and hepcidin levels of normal individuals and the TMPRSS6 common single nucleotide polymorphism (rs855791) 29 we demonstrated that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis.The regulation of TMPRSS6 and its activity is incompletely understood: besides hypoxia, 30 iron and BMP6, through the BMP-SMAD pathway, induce TMPRSS6 expression, likely as a negative feedback loop to limit excessive increases of HAMP. 31 However, the regulation of TMPRSS6 in vivo according to iron needs remains to be clarified.…”

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confidence: 99%

The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nvariants associate with iron and erythrocyte traits in different populations. [22][23][24][25][26][27] By studying Tmprss6 haploinsufficient mice 28 and hepcidin levels of normal individuals and the TMPRSS6 common single nucleotide polymorphism (rs855791) 29 we demonstrated that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis.The regulation of TMPRSS6 and its activity is incompletely understood: besides hypoxia, 30 iron and BMP6, through the BMP-SMAD pathway, induce TMPRSS6 expression, likely as a negative feedback loop to limit excessive increases of HAMP. 31 However, the regulation of TMPRSS6 in vivo according to iron needs remains to be clarified. A possible role of Tmprss6 in iron overload was demonstrated by Finberg et al. 32 who showed that Hfe -/-mice with complete loss of Tmprss6 revert from a phenotype of iron overload to one of iron-deficiency anemia with high Hamp levels. These findings suggest that HFE acts genetically upstream of TMPRSS6 in the modulation of the BMP-SMAD pathway and of HAMP expression. In analogy with these results and given the role of TFR2 in erythropoiesis 16 we wondered whether TFR2 is involved in the regulation of TMPRSS6. To answer this question, we back-crossed Tmprss6 -/-mice with animals with a complete deletion of Tfr2 (Tfr2 -/-) and analyzed the hematologic phenotype and the Bmp-Smad-Hamp pathway of the double mutant mice. Moreover, in order to discriminate between the hepatic and extra-hepatic functions of TFR2, we performed the same analysis in Tmprss6 -/-mice lacking Tfr2 specifically in the liver (Tfr2 LCKO ). 15 Methods Mouse modelsMice were maintained in the animal facility of the Department of Clinical and Biological Sciences, University of Turin (Italy) in accordance with European Union guidelines. Each study was approved by the Institutional Animal Care and Use Committee (IACUC) of the same institution.A Tmprss6 -/-mouse model on a mixed C57BL/6-Sv129 background was kindly provided by Prof. C. Lopez-Otin (University of Oviedo, Spain) and maintained by brother-sister mating for more than ten generations. Tfr2 -/-and Tfr2 LCKO mice on a pure 129S2 background were generated as previously described. 15 For the experimental work described we bred Tfr2 -/-or Tfr2 LCKO mice with Tmprss6 +/-mice and then intercrossed the F1 progeny to generate various genotype combinations (F2: wild-type, Tmprss6. Mice were given a standard diet (480 mg iron/Kg) and only male mice were analyzed when 10 weeks old. Blood was collected for hematologic analyses, transferrin saturation and erythropoietin levels. After sacrifice livers and spleens were dissected, weighed, and snap-frozen immediately for RNA analysis or dried for tissue iron quantification. Hematologic analysesBlood was obtained by retro-orbital puncture from anesthetized mice. Red blood cell and white blood cell counts, hemoglobin concentration, hematocrit and erythrocyte indices (mean corpuscular volume, mean cor...

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“…In animal models, haploinsufficiency of Tmprss6 confers susceptibility to iron deficiency. 58,59 The association between a deleterious mutation and a low expressed allele has been found in several inherited disorders such as erythropoietic protoporphyria, 60 spherocytosis 61 or microcytic anemia due to STEAP3 mutations. 62 This might be a rather frequent situation since recent reports have demonstrated that preferential/specific allele expression may concern 5-20% of the genes.…”

Section: Irida Phenotype With a Single Or No Mt-2 Mutation: The Case mentioning

confidence: 99%

Iron refractory iron deficiency anemia

et al. 2013

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Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein. In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia. In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment. A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients. The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration; in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach

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Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice

Abstract: References

Cited by 24 publications

References 10 publications

Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice

Iron refractory iron deficiency anemia

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