Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6

Abstract 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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An Essential Role For Transferrin Receptor 2 In Erythropoiesis During Iron Restriction

Blood ◽

10.1182/blood.v122.21.429.429 ◽

2013 ◽

Vol 122 (21) ◽

pp. 429-429

Author(s):

Daniel F Wallace ◽

Cameron J McDonald ◽

Eriza S Secondes ◽

Lesa Ostini ◽

Gautam Rishi ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Iron Deficiency Anemia ◽

Transferrin Receptor ◽

Iron Homeostasis ◽

Hereditary Hemochromatosis ◽

Deficiency Anemia ◽

Erythroid Cells ◽

Iron Restriction ◽

Extramedullary Erythropoiesis

Abstract Iron deficiency and iron overload are common clinical conditions that impact on the health and wellbeing of up to 30% of the world’s population. Understanding mechanisms regulating iron homeostasis will provide improved strategies for treating these disorders. The liver-expressed proteins matriptase-2 (encoded by TMPRSS6), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis by regulating expression of the iron regulatory hormone hepcidin. Mutations in TMPRSS6 lead to iron refractory iron deficiency anemia, whereas mutations in HFE and TFR2 lead to the iron overload disorder hereditary hemochromatosis. To elucidate the competing roles of these hepcidin regulators, we created mice lacking matriptase-2, Hfe and Tfr2. Tmprss6 -/-/Hfe-/-/Tfr2-/- mice had iron deficiency anemia resulting from hepatic hepcidin over-expression and activation of Smad1/5/8, indicating that matriptase-2 predominates over Hfe and Tfr2 in hepcidin regulation. Surprisingly, this anemia was more severe than in the Tmprss6-/- mice, demonstrated by more extensive alopecia, lower hematocrit and significant extramedullary erythropoiesis in the spleen. There was increased expression of erythroid-specific genes in the spleens of Tmprss6-/-/Hfe-/-/Tfr2-/- mice, consistent with the extramedullary erythropoiesis. Expression of Tfr2 but not Hfe in the spleen was increased in the Tmprss6-/- mice compared to wild type and correlated with the expression of erythroid genes, suggesting that Tfr2 is expressed in erythroid cells. Further analysis of gene expression in the bone marrow suggests that the loss of Tfr2 in the erythroid cells of Tmprss6-/-/Hfe-/-/Tfr2-/- mice causes a delay in the differentiation process leading to a more severe phenotype. In conclusion, our results indicate that Hfe and Tfr2 act upstream of matriptase-2 in hepcidin regulation or in a way that is overridden when matriptase-2 is deleted. These results indicate that inhibition of matriptase-2 would be useful in the treatment of iron overload conditions such as hereditary hemochromatosis. We have also identified a novel role for Tfr2 in erythroid differentiation that is separate from its canonical role as a regulator of iron homeostasis in the liver. This important role of Tfr2 in erythropoiesis only becomes apparent during conditions of iron restriction. Our results provide novel insights into mechanisms regulating and linking iron homeostasis and erythropoiesis. Disclosures: No relevant conflicts of interest to declare.

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A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Communications Biology ◽

10.1038/s42003-020-01575-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Steven Bell ◽

◽

Andreas S. Rigas ◽

Magnus K. Magnusson ◽

Egil Ferkingstad ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Iron Deficiency Anemia ◽

Iron Homeostasis ◽

Meta Analysis ◽

Deficiency Anemia ◽

Genome Wide Association Studies ◽

Independent Sequence ◽

Genome Wide ◽

A Genome

AbstractIron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

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The Relationship between Iron deficiency anemia and Febrile Convulsions in infant and Children

Zagazig University Medical Journal ◽

10.21608/zumj.2020.21787.1669 ◽

2020 ◽

Vol 0 (0) ◽

pp. 0-0

Author(s):

fatima shaaib ◽

Asmaa Esh ◽

Seham Azab ◽

sahbaa hafez

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Deficiency Anemia ◽

Febrile Convulsions ◽

The Relationship

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Iron Homeostasis and Disorders in Dogs and Cats: A Review

Journal of the American Animal Hospital Association ◽

10.5326/jaaha-ms-5553 ◽

2011 ◽

Vol 47 (3) ◽

pp. 151-160 ◽

Cited By ~ 27

Author(s):

Jennifer L. McCown ◽

Andrew J. Specht

Keyword(s):

Iron Deficiency ◽

Iron Overload ◽

Iron Homeostasis ◽

Diagnostic Testing ◽

Clinical Manifestations ◽

Essential Element ◽

The Body ◽

Deficiency Anemia ◽

Enzyme Systems ◽

Living Organisms

Iron is an essential element for nearly all living organisms and disruption of iron homeostasis can lead to a number of clinical manifestations. Iron is used in the formation of both hemoglobin and myoglobin, as well as numerous enzyme systems of the body. Disorders of iron in the body include iron deficiency anemia, anemia of inflammatory disease, and iron overload. This article reviews normal iron metabolism, disease syndromes of iron imbalance, diagnostic testing, and treatment of either iron deficiency or excess. Recent advances in diagnosing iron deficiency using reticulocyte indices are reviewed.

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Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1715302115 ◽

2018 ◽

Vol 115 (12) ◽

pp. 3000-3005 ◽

Cited By ~ 7

Author(s):

Benjamin H. Hudson ◽

Andrew T. Hale ◽

Ryan P. Irving ◽

Shenglan Li ◽

John D. York

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Iron Reduction ◽

Genetic Basis ◽

Iron Homeostasis ◽

Deficiency Anemia ◽

Sulfur Assimilation ◽

Nucleotide Hydrolysis ◽

Evolutionarily Conserved ◽

Organismal Development

Sulfur assimilation is an evolutionarily conserved pathway that plays an essential role in cellular and metabolic processes, including sulfation, amino acid biosynthesis, and organismal development. We report that loss of a key enzymatic component of the pathway, bisphosphate 3′-nucleotidase (Bpnt1), in mice, both whole animal and intestine-specific, leads to iron-deficiency anemia. Analysis of mutant enterocytes demonstrates that modulation of their substrate 3′-phosphoadenosine 5′-phosphate (PAP) influences levels of key iron homeostasis factors involved in dietary iron reduction, import and transport, that in part mimic those reported for the loss of hypoxic-induced transcription factor, HIF-2α. Our studies define a genetic basis for iron-deficiency anemia, a molecular approach for rescuing loss of nucleotidase function, and an unanticipated link between nucleotide hydrolysis in the sulfur assimilation pathway and iron homeostasis.

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Liver iron sensing and body iron homeostasis

Blood ◽

10.1182/blood-2018-06-815894 ◽

2019 ◽

Vol 133 (1) ◽

pp. 18-29 ◽

Cited By ~ 45

Author(s):

Chia-Yu Wang ◽

Jodie L. Babitt

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Inflammatory Diseases ◽

Genetic Disorders ◽

Hereditary Hemochromatosis ◽

Deficiency Anemia ◽

Iron Loading ◽

Liver Iron ◽

Body Iron ◽

Iron Supply

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

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Molecular Aspects and Treatment of Iron Deficiency in the Elderly

International Journal of Molecular Sciences ◽

10.3390/ijms21113821 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3821

Author(s):

Antonino Davide Romano ◽

Annalisa Paglia ◽

Francesco Bellanti ◽

Rosanna Villani ◽

Moris Sangineto ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Iron Homeostasis ◽

Diagnostic Algorithm ◽

The Elderly ◽

Deficiency Anemia ◽

Clinical State ◽

Ageing Population ◽

Gastrointestinal Lesions ◽

Aged Subjects

Iron deficiency (ID) is the most frequent nutritional deficiency in the whole population worldwide, and the second most common cause of anemia in the elderly. The prevalence of anemia is expecting to rise shortly, because of an ageing population. Even though WHO criteria define anemia as a hemoglobin serum concentration <12 g/dL in women and <13 g/dL in men, several authors propose different and specific cut-off values for the elderly. Anemia in aged subjects impacts health and quality of life, and it is associated with several negative outcomes, such as longer time of hospitalization and a higher risk of disability. Furthermore, it is an independent risk factor of increased morbidity and mortality. Even though iron deficiency anemia is a common disorder in older adults, it should be not considered as a normal ageing consequence, but a sign of underlying dysfunction. Relating to the molecular mechanism in Iron Deficiency Anemia (IDA), hepcidin has a key role in iron homeostasis. It downregulates the iron exporter ferroportin, inhibiting both iron absorption and release. IDA is frequently dependent on blood loss, especially caused by gastrointestinal lesions. Thus, a diagnostic algorithm for IDA should include invasive investigation such as endoscopic procedures. The treatment choice is influenced by the severity of anemia, underlying conditions, comorbidities, and the clinical state of the patient. Correction of anemia and iron supplementation should be associated with the treatment of the causal disease.

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