New and old players in the hepcidin pathway

Camaschella, Clara; Silvestri, Laura

doi:10.3324/haematol.13724

Cited by 29 publications

(18 citation statements)

References 32 publications

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“…20,23,33,34 In the current studies, we tested BMP6, known to be a critical BMP signaling ligand for the regulation of hepcidin in vivo. 18,35 Our observations in hepatocyte-derived lines confirm the previously described connection between BMP signaling-and IL-6-mediated regulation of hepcidin gene expression. 24,28,36-38 Neither IL-6 nor turpentine directly activated the BMP signaling pathway, as assessed by measuring phosphorylation of SMAD1/5/8.…”

Section: Org Fromsupporting

confidence: 79%

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Steinbicker

Sachidanandan

Vonner

et al. 2011

Blood

160

157

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Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189 IntroductionAnemia of inflammation (AI), also known as anemia of chronic disease (ACD), is the most prevalent form of anemia after iron-deficient anemia (IDA). 1,2 AI frequently occurs in patients with a broad array of infectious, autoimmune, or inflammatory disorders, as well as cancer and kidney disease, and can contribute to the morbidity associated with these conditions. 3 In contrast to IDA, AI is typically normochromic and normocytic with hemoglobin (Hb) levels greater than 8 g/dL; however, severe AI can lead to microcytosis. 1,2 Patients with AI have diminished serum iron levels and transferrin saturations, whereas ferritin levels are normal or elevated. 3 Erythropoietin levels are typically elevated, but lower than those seen in patients with a similar degree of anemia attributable to iron deficiency. While a mild degree of anemia may be tolerated in patients who are otherwise healthy, anemia in patients with cardiovascular or pulmonary disease can impair systemic oxygen delivery, thereby worsening angina or dyspnea, or reducing exercise tolerance. Moreover, anemia is associated with worsened prognosis in cancer, 4 chronic kidney disease, 5-7 and congestive heart failure. 5,8,9 When treatment of the underlying disease is incomplete or not feasible, blood transfusions, erythropoiesis-stimulating agents (ESAs), and iron supplementation have been used to increase Hb levels in AI. However, there are known risks associated with blood transfusion, and iron supplementation in AI requires intravenous (IV) administration. Moreover, aggressive treatment with ESAs can increase the cardiovascular events and mortality in patients with kidney disease 10 and may accelerate tumor progression in patients with cancer. 11 Thus, additional therapeutic options are needed for patients with AI.A common feature of the disorders associated with AI is immune activation and production of inflammatory cytokines, such as IL-1␤, IL-6, TNF␣, and IFN␥. IL-6 is especially potent in regulating the expression of the peptide hormone hepcidin, a central regulator of systemic iron balance. [12][13][14][15] Hepcidin binds to and initiates degradation of ferroportin-1, the sole elemental iron exporter...

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Section: Org Fromsupporting

confidence: 79%

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Steinbicker

Sachidanandan

Vonner

et al. 2011

Blood

160

157

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“…Mutations in the gene encoding hepcidin (HAMP) effectively mimic an iron deficiency situation and lead to an increase in iron absorption and a severe early onset iron overload disease known as juvenile hemochromatosis. Mutations in several other genes, including those encoding hemojuvelin (HJV), HFE and transferrin receptor 2 (TfR2) also lead to iron loading syndromes that are phenotypically very similar to that associated with hepcidin deficiency (although the disease severity may vary), and these disorders do indeed have low or absent hepcidin expression [8]. Thus, hepcidin, HJV, HFE and TfR2 are all parts of the same regulatory pathway, with HJV, HFE and TfR2 being upstream regulators of hepcidin.…”

Section: Systemic Regulation Of Iron Absorptionmentioning

confidence: 97%

Iron absorption and metabolism

Anderson

Frazer²,

McLaren³

2009

Current Opinion in Gastroenterology

166

102

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“…An integral player in regulating body iron supply in response to its requirements is the hepatic peptide hormone, hepcidin. 79,80 Hepcidin mediates the internalization and degradation of the iron export molecule ferroportin, located on the surface of intestinal enterocytes, macrophages and hepatocytes, thereby negatively regulating iron entry into the plasma. 81 Consistently, mice deficient in hepcidin 82 and humans with mutations of this gene develop severe iron overload disorders.…”

Section: Systemic Iron Regulation By Matriptase-2mentioning

confidence: 99%

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

Ramsay¹,

Hooper²,

Folgueras³

et al. 2009

Haematologica

110

104

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Maintaining the body's levels of iron within precise boundaries is essential for normal physiological function. Alterations of these levels below or above the healthy limit lead to a systemic deficiency or overload in iron. The type-two transmembrane serine protease (TTSP), matriptase-2 (also known as TMPRSS6), is attracting significant amounts of interest due to its recently described role in iron homeostasis. The finding of this regulatory role for matriptase-2 was originally derived from the observation that mice deficient in this protease present with anemia due to elevated levels of hepcidin and impaired intestinal iron absorption. Further in vitro analysis has demonstrated that matriptase-2 functions to suppress bone morphogenetic protein stimulation of hepcidin transcription through cell surface proteolytic processing of the bone morphogenetic protein co-receptor hemojuvelin. Consistently, the anemic phenotype of matriptase-2 knockout mice is mirrored in humans with matripase-2 mutations. Currently, 14 patients with iron-refractory iron deficiency anemia (IRIDA) have been reported to harbor various genetic mutations that abrogate matriptase-2 proteolytic activity. In this review, after overviewing the membrane anchored serine proteases, in particular the TTSP family, we summarize the identification and characterization of matriptase-2 and describe its functional relevance in iron metabolism.

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New and old players in the hepcidin pathway

Cited by 29 publications

References 32 publications

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Iron absorption and metabolism

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

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