Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin

Kent, Patricia; Wilkinson, Nicole; Constante, Marco; Fillebeen, Carine; Gkouvatsos, Konstantinos; Wagner, John; Buffler, Marzell; Becker, Christiane; Schümann, Klaus; Santos, Manuela M.; Pantopoulos, Kostas

doi:10.1007/s00109-015-1253-7

Cited by 32 publications

(43 citation statements)

References 36 publications

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“…This was demonstrated in mice subjected to meniscus destabilization, namely the aggravation of OA phenotype in Hfe ‐KO mice when compared with wt group (Figure a), with evidence of significant iron accumulation in synovial tissues of Hfe ‐KO mice . HFE effect on iron overload is connected with the downregulation of hepcidin expression (mainly specific to liver), which can favor dietary iron absorption and ferroportin iron exportation to plasma, resulting in systemic iron overload . In addition, HFE loss of function can lead to increased intracellular iron absorption .…”

Section: Discussionmentioning

confidence: 91%

Intracellular iron uptake is favored in Hfe‐KO mouse primary chondrocytes mimicking an osteoarthritis‐related phenotype

et al. 2019

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HFE‐hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE‐hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe‐KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild‐type (wt) mice. Our data provide evidence that both wt‐ and Hfe‐KO‐derived chondrocytes, when exposed to 50 μM iron, develop characteristics of an OA‐related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe‐KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 μM iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex‐determining region Y)‐box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA‐related phenotype.

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Section: Discussionmentioning

confidence: 91%

Intracellular iron uptake is favored in Hfe‐KO mouse primary chondrocytes mimicking an osteoarthritis‐related phenotype

et al. 2019

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“…15,16 Wu et al's study further demonstrated that Hjv −/− mice exhibited more severe iron overload, compared with Hfe −/− mice, but similar to Hfe −/− Hjv −/− mice. 17,18 Wu et al's study also uncovered that mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase does not play a prominent role in this process. 17 Overall, these results indicate that HFE is involved in hepcidin regulation in an HJV-dependent manner.…”

Section: Molecular Basis Of Systemic Iron Homeostasismentioning

confidence: 99%

Hepcidin

et al. 2016

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Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and β-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and β-thalassemia), hepatic hepcidin concentration is significantly reduced.Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin.Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated.Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve β-thalassemia phenotypes by improving ineffective erythropoiesis. Relative to the current conventional therapies, such as phlebotomy and blood transfusion, therapeutics targeting hepcidin would open a new avenue for treatment of iron-related diseases.

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“…The authors suggest that Hfe and Hjv genes lead to an overlapping function in signaling to expression of hepcidin. Wu were not yet published at the time of this writing [9,10]. Do the papers differ?…”

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confidence: 99%

“…In this issue of J Mol Med, Kent et al also argue that HFE and HJV display overlapping functions to regulate hepcidin [10]. They also investigated Hfe and Hjv gene-deficient mice.…”

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confidence: 99%