Abstract
Iron‐refractory iron deficiency anemia (IRIDA) is an autosomal recessive disorder caused by genetic mutations on TMPRSS6 gene which encodes Matriptase2 (MT2). An altered MT2 cannot appropriately suppress hepatic BMP6/SMAD signaling in case of low iron, hence hepcidin excess blocks dietary iron absorption, leading to a form of anemia resistant to oral iron supplementation. In this study, using the IRIDA mouse model Mask, we characterized homozygous (msk/msk) compared to asymptomatic heterozygous (msk/wt) mice, assessing the major parameters of iron status in different organs, at different ages in both sexes. The effect of carbonyl iron diet was analyzed as control iron supplementation being used for many studies in mice. It resulted effective in both anemic control and msk/msk mice, as expected, even if there is no information about its mechanism of absorption. Then, we mainly compared two forms of oral iron supplement, largely used for humans: ferrous sulfate and Sucrosomial iron. In anemic control mice, the two oral formulations corrected hemoglobin levels from 11.40 ± 0.60 to 15.38 ± 1.71 g/dl in 2–4 weeks. Interestingly, in msk/msk mice, ferrous sulfate did not increase hemoglobin likely due to ferroportin/hepcidin‐dependent absorption, whereas Sucrosomial iron increased it from 11.50 ± 0.60 to 13.53 ± 0.64 g/dl mainly in the first week followed by a minor increase at 4 weeks with a stable level of 13.30 ± 0.80 g/dl, probably because of alternative absorption. Thus, Sucrosomial iron, already used in other conditions of iron deficiency, may represent a promising option for oral iron supplementation in IRIDA patients.
Highlights
Hepcidin is the main regulator of systemic iron homeostasis reducing iron absorption, its recycling and mobilization from stores by the promotion of ferroportin (FPN) internalization and degradation.[1,2] Liver hepcidin expression is regulated by various factors, mostly connected with iron availability mainly by bone morphogenetic protein 6 (BMP6), inflammation by Interleukin 6 (IL6), hypoxia by hypoxia-inducible factor 2α (HIF2α), and erythropoietic activity by Erythroferrone (ERFE).[3,4,5]Note, BMP6, produced by liver non-parenchymal cells,[6,7,8] interacts with its receptors and the co-receptor hemojuvelin (HJV), participating in BMP/SMAD1/5/8 signaling
An altered MT2 cannot appropriately suppress hepatic BMP6/SMAD signaling in case of low iron, hepcidin excess blocks dietary iron absorption, leading to a form of anemia resistant to oral iron supplementation
It has been reported that MT2 cleaves BMP receptors (BMPR) ALK2, ALK3, ActRIIa, BMPR2, the homeostatic iron regulator protein (HFE) and transferrin receptor 2 (Tfr2)[13] on the cell membrane, revealing a complex function
Summary
Hepcidin is the main regulator of systemic iron homeostasis reducing iron absorption, its recycling and mobilization from stores by the promotion of ferroportin (FPN) internalization and degradation.[1,2] Liver hepcidin expression is regulated by various factors, mostly connected with iron availability mainly by bone morphogenetic protein 6 (BMP6), inflammation by Interleukin 6 (IL6), hypoxia by hypoxia-inducible factor 2α (HIF2α), and erythropoietic activity by Erythroferrone (ERFE).[3,4,5]. We studied the homozygous (msk/msk) and heterozygous (msk/wt) Mask mouse strain[16] (males and females) from 3 to 28 weeks of age, by following iron content in several tissues, body weight, hepcidin, serum iron, hemoglobin (Hb), hematocrit (Ht) and some markers of BMP6/SMAD pathway and inflammation. This allowed to select the 9-weeks old mice (when the main hematological and iron parameters were stabilized) as the best period to evaluate the effects of Ferrous sulfate and Sucrosomial iron, in order to investigate possible differences in iron absorption and to identify the best strategy to treat IRIDA disease
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