CD81 Promotes Both the Degradation of Transferrin Receptor 2 (TfR2) and the Tfr2-mediated Maintenance of Hepcidin Expression

Chen, Juxing; Enns, Caroline A.

doi:10.1074/jbc.m114.632778

Cited by 14 publications

(11 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TfR2 is predominantly expressed in liver cells and is able to positively regulate the BMP signaling pathway to upregulate hepcidin expression. The TfR2 gene mutation is one of the causes of hereditary hemochromatosis ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

A composite mouse model of aplastic anemia complicated with iron overload

Wen

Liu

et al. 2017

Exp Ther Med

View full text Add to dashboard Cite

Iron overload is commonly encountered during the course of aplastic anemia (AA), but no composite animal model has been developed yet, which hinders drug research. In the present study, the optimal dosage and duration of intraperitoneal iron dextran injection for the development of an iron overload model in mice were explored. A composite model of AA was successfully established on the principle of immune-mediated bone marrow failure. Liver volume, peripheral hemogram, bone marrow pathology, serum iron, serum ferritin, pathological iron deposition in multiple organs (liver, bone marrow, spleen), liver hepcidin, and bone morphogenetic protein 6 (BMP6), SMAD family member 4 (SMAD4) and transferrin receptor 2 (TfR2) mRNA expression levels were compared among the normal control, AA, iron overload and composite model groups to validate the composite model, and explore the pathogenesis and features of iron overload in this model. The results indicated marked increases in iron deposits, with significantly increased liver/body weight ratios as well as serum iron and ferritin in the iron overload and composite model groups as compared with the normal control and AA groups (P<0.05). There were marked abnormalities in iron regulation gene expression between the AA and composite model groups, as seen by the significant decrease of hepcidin expression in the liver (P<0.01) that paralleled the changes in BMP6, SMAD4, and TfR2. In summary, a composite mouse model with iron overload and AA was successfully established, and AA was indicated to possibly have a critical role in abnormal iron metabolism, which promoted the development of iron deposits.

show abstract

Section: Discussionmentioning

confidence: 99%

A composite mouse model of aplastic anemia complicated with iron overload

Wen

Liu

et al. 2017

Exp Ther Med

View full text Add to dashboard Cite

show abstract

“…This occurs also in erythroid cells (UT7) and ex vivo in erythroblasts differentiated in culture . We have proposed that in iron deficiency, TFR2 releases a soluble isoform from plasma membrane , while others have suggested an increased degradation . Lack of TFR2 on the erythroblast surface, irrespective of how it is achieved, increases both EPO sensitivity and ERFE expression .…”

Section: The Inverse Relationshipmentioning

confidence: 99%

The mutual control of iron and erythropoiesis

Camaschella

Pagani

Nai

et al. 2016

Int J Lab Hematology

View full text Add to dashboard Cite

Summary Background Iron is essential for hemoglobin synthesis during terminal erythropoiesis. To supply adequate iron the carrier transferrin is required together with transferrin receptor endosomal cycle and normal mitochondrial iron utilization. Iron and iron protein deficiencies result in different types of anemia. Iron‐deficiency anemia is the commonest anemia worldwide due to increased requirements, malnutrition, chronic blood losses and malabsorption. Mutations of transferrin, transferrin receptor cycle proteins, enzymes of the first step of heme synthesis and iron sulfur cluster biogenesis lead to rare anemias, usually accompanied by iron overload. Hepcidin plays an indirect role in erythropoiesis by controlling plasma iron. Inappropriately high hepcidin levels characterize the rare genetic iron‐refractory iron‐deficiency anemia (IRIDA) and the common anemia of chronic disease. Iron modulates both effective and ineffective erythropoiesis: iron restriction reduces heme and alpha‐globin synthesis that may be of benefit in thalassemia. Material and Methods This review relies on the analysis of the most recent literature and personal data. Results Erythropoiesis controls iron homeostasis, by releasing erythroferrone that inhibits hepcidin transcription to increase iron acquisition in iron deficiency, hypoxia and EPO treatment. Erythroferrone, produced by EPO‐stimulated erythropoiesis, inhibits hepcidin only when the activity of BMP/SMAD pathway is low, suggesting that EPO somehow modulates the latter signaling. Erythroblasts sense circulating iron through the second transferrin receptor (TFR2) that, in animal models, modulates the sensitivity of the erythroid cells to EPO. Discussion The advanced knowledge of the regulation of systemic iron homeostasis and erythropoiesis‐mediated hepcidin regulation is leading to the development of targeted therapies for anemias and iron disorders.

show abstract

“… 31 TfR2, which is highly expressed in liver, can also positively regulate the BMP signaling pathway and upregulate hepcidin gene expression. 32 In our mice model, iron-overload AA was characterized by a heavy iron deposition in liver and bone marrow and by a significantly higher expression of SI and SF and lower expression of hepcidin as well as its positive regulatory factors (BMP-6, SMAD4, and TfR2). Iron chelation can reverse this, that is, DFX has a better effect in upregulation of BMP-6 and TfR2, while the combined treatment has a more significant effect in reducing the SI and SF and increasing the expression of serum BMP-6, liver hepcidin, and SMAD4.…”

Section: Discussionmentioning

confidence: 87%

Comparison of the effects of deferasirox, deferoxamine, and combination of deferasirox and deferoxamine on an aplastic anemia mouse model complicated with iron overload

Wen

Liu

et al. 2018

DDDT

View full text Add to dashboard Cite

Background and aimIron overload is commonly observed during the course of aplastic anemia (AA), which is believed to aggravate hematopoiesis, cause multiple organ dysfunction, lead to disease progression, and impair quality of life. Deferasirox (DFX) and deferoxamine (DFO) are among the most common iron chelation agents available in the clinical setting. The aim of this study was to investigate if the combination therapy with DFX and DFO is superior in hematopoietic recovery and iron chelation.MethodsBriefly, we developed a composite mouse model with AA and iron overload that was consequently treated with DFX, DFO, or with a combination of both agents. The changes in peripheral hemogram, marrow apoptosis, and its related protein expressions were compared during the process of iron chelation, while the iron depositions in liver and bone marrow and its regulator were also detected.ResultsThe obtained results showed that compared to DFX, DFO has a better effect in protecting the bone marrow from apoptosis-induced failure. The combination of DFO and DFX accelerated the chelation of iron, while their efficiency on further hemogram improvement appeared limited.ConclusionTo sum up, our data suggest that single treatment with DFO may be a better choice for improving the hematopoiesis during the gradual chelation treatment irrespective of the convenience of oral DFX, while the combination treatment should be considered for urgent reduction of the iron burden.

show abstract

CD81 Promotes Both the Degradation of Transferrin Receptor 2 (TfR2) and the Tfr2-mediated Maintenance of Hepcidin Expression

Cited by 14 publications

References 55 publications

A composite mouse model of aplastic anemia complicated with iron overload

A composite mouse model of aplastic anemia complicated with iron overload

The mutual control of iron and erythropoiesis

Comparison of the effects of deferasirox, deferoxamine, and combination of deferasirox and deferoxamine on an aplastic anemia mouse model complicated with iron overload

Contact Info

Product

Resources

About