Modulation of hepcidin to treat iron deregulation: potential clinical applications

Blanchette, Nicole; Manz, David H.; Torti, Frank M.; Torti, Suzy V.

doi:10.1586/17474086.2016.1124757

Cited by 50 publications

(41 citation statements)

References 147 publications

(182 reference statements)

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“…SOSTDC1 antagonizes BMP signalling by sequestering BMP-like linkers, similar to sHJV [132,193]. The soluble portion of HJV was fused to the Fc portion of an IgG, resulting in sHJV.Fc, which binds to BMPr, inhibiting the transcription of the HAMP gene via the BMP6/SMAD pathway [194].…”

Section: Hepcidinmentioning

confidence: 99%

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Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

et al. 2017

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Iron is an essential metal for cell survival that is regulated by the peptide hormone hepcidin. However, its influence on certain diseases is directly related to iron metabolism or secondary to underlying diseases. Genetic alterations influence the serum hepcidin concentration, which can lead to an iron overload in tissues, as observed in haemochromatosis, in which serum hepcidin or defective hepcidin synthesis is observed. Another genetic imbalance of iron is iron-refractory anaemia, in which serum concentrations of hepcidin are increased, precluding the flow and efflux of extra- and intracellular iron. During the pathogenesis of certain diseases, the resulting oxidative stress, as well as the increase in inflammatory cytokines, influences the transcription of the HAMP gene to generate a secondary anaemia due to the increase in the serum concentration of hepcidin. To date, there is no available drug to inhibit or enhance hepcidin transcription, mostly due to the cytotoxicity described in the in vitro models. The proposed therapeutic targets are still in the early stages of clinical trials. Some candidates are promising, such as heparin derivatives and minihepcidins. This review describes the main pathways of systemic and genetic regulation of hepcidin, as well as its influence on the disorders related to iron metabolism.

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Section: Hepcidinmentioning

confidence: 99%

“…Thus, fursultiamine prevents the interaction between ferroportin-hepcidin by sequestering the Cys326-HS residue and blocking the internalization of hepcidin ferroportin [195]. Another humanized antibody was developed for the same purpose, LY2928057, which is currently in phase I clinical trials of haemodialysis patients [193]. …”

Section: Hepcidinmentioning

confidence: 99%

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

et al. 2017

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“…Several types of reagents have been developed for this purpose and are in various stages of pre-clinical or clinical evaluation. 101,102 One approach to inhibiting hepcidin expression is to block activation of the BMP signaling pathway. Soluble forms of the BMP co-receptor HJV have been shown to correct hypoferremia and ameliorate anemia in rodent models of AI, including in a mouse model of IBD.…”

Section: Management Of Anemia In Ibdmentioning

confidence: 99%

Iron and inflammation – the gut reaction

Verma

Cherayil

2017

Metallomics

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Anemia is a frequent complication of many inflammatory disorders, including inflammatory bowel disease. Although the pathogenesis of this problem is multifactorial, a key component is the abnormal elevation of the hormone hepcidin, the central regulator of systemic iron homeostasis. Investigations over the last decade have resulted in important insights into the role of hepcidin in iron metabolism and the mechanisms that lead to hepcidin dysregulation in the context of inflammation. These insights provide the foundation for novel strategies to prevent and treat the anemia associated with inflammatory diseases.

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“…Inappropriate synthesis of hepcidin contributes to a number of pathological conditions, notably the Anemia of Chronic Disease (ACD), iron-refractory iron deficiency anemia, and the anemia associated with chronic kidney disease [2,3]. The widespread prevalence of these conditions, particularly ACD, has led to the search for pharmacological inhibitors of hepcidin, a number of which are currently being tested in clinical trials [4].…”

Section: Introductionmentioning

confidence: 99%

Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts

Lemler

Bk³

et al. 2016

Clin Exp Pharmacol

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Objective Hepcidin is a peptide hormone produced by the liver that regulates systemic iron homeostasis. Hepcidin is also synthesized by tumors, where it contributes to tumor growth by increasing the tumoral retention of iron. Targeted reduction of hepcidin may therefore be useful in reducing tumor growth. H5F9-AM8 is an antibody in preclinical development for the anemia of chronic disease that reduces hepcidin synthesis by binding to RGMc, a co-receptor involved in the transcriptional induction of hepcidin by BMP6. We explored the ability of H5F9-AM8 to act as an anti-tumor agent. Methods Effects of anti-hemojuvelin antibody on hepcidin synthesis were assessed by qRTPCR in tissue culture and in tumor xenografts and livers of mice treated with H5F9-AM8 or saline. Tumor growth was assessed using caliper measurements. Serum iron was measured colorimetrically and tissue iron was measured using western blotting and inductively coupled mass spectrometry. Results In tissue culture, the anti-hemojuvelin antibody H5F9-AM8 significantly reduced BMP6-stimulated hepcidin synthesis in HepG2 and other cancer cells. In mice, H5F9-AM8 reduced hepcidin in the liver and increased serum iron, total liver iron, and liver ferritin. Although hepcidin in tumors was also significantly decreased, H5F9-AM8 did not reduce tumor iron content, ferritin, or tumor growth. Conclusion Anti-hemojuvelin antibody successfully reduces hepcidin in both tumors and livers but has different effects in these target organs: it reduces iron content and ferritin in the liver, but does not reduce iron content or ferritin in tumors, and does not inhibit tumor growth. These results suggest that despite their ability to induce hepcidin in tumors, the anti-tumor efficacy of systemic, non-targeted hepcidin antagonists may be limited by their ability to simultaneously elevate plasma iron. Tumor-specific hepcidin inhibitors may be required to overcome the limitations of drugs that target the synthesis of both systemic and tumor hepcidin.

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Modulation of hepcidin to treat iron deregulation: potential clinical applications

Cited by 50 publications

References 147 publications

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

Iron and inflammation – the gut reaction

Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts

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