Hepcidin and the BMP-SMAD pathway: An unexpected liaison

Silvestri, Laura; Nai, Antonella; Dulja, Alessandro; Pagani, Alessia

doi:10.1016/bs.vh.2019.01.004

Cited by 91 publications

(94 citation statements)

References 107 publications

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“…The results of this study showed that the CRP, hepcidin, and SF levels in the elevated CRP group were higher than the normal CRP group, but the Hb level was lower (P < 0.05), suggesting that the higher the inflammation level, the more severe the anemia. Some studies have confirmed that the inflammatory factor pathways and the BMP-SMAD signaling pathway have synergistic effects in inducing the expression of hepcidin and BMP6 and HJV deficiency may attenuate the roles of inflammatory pathways [20][21][22][23]. But in our group, the levels of BMP6 in the two subgroups had no obvious disparity.…”

Section: Discussionmentioning

confidence: 47%

Expression of serum BMP6 and hepcidin in cancer-related anemia

Zhang

Yan

et al. 2020

Hematology

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Objective: To study the function of human bone morphogenetic protein-6 (BMP6) and hepcidin in cancer-related anemia. Methods: The levels of Hemoglobin (Hb), serum C-reactive protein (CRP), BMP6, hepcidin and ferritin (SF) were measured in 115 patients with solid tumors, who were divided into elevated CRP group and normal CRP group, and further divided into anemia subgroup and non-anemia subgroup according to the CRP level. Results: The prevalence of anemia was 53.9% in all patients. In the elevated CRP group, the levels of CRP, hepcidin and SF of the anemia subgroup were higher than the non-anemia subgroup (P < 0.05); the BMP6 levels had no difference between the subgroups (P > 0.05). In the normal CRP group, the BMP6 level in the anemia subgroup was higher than the nonanemia subgroup (P < 0.01); the CRP, hepcidin and SF levels showed no difference between the subgroups (P > 0.05). Among the 115 patients, CRP and SF were both positively correlated with hepcidin (P < 0.05), and CRP and hepcidin were negatively correlated with Hb (P < 0.05), while SF had no correlation with Hb (P > 0.05); BMP6 was negatively correlated with Hb (P < 0.05) while had no correlation with CRP, hepcidin and SF (P < 0.05). Conclusions: The occurrence of anemia in patients with elevated CRP is associated with hepcidin over-expression, while in patients with normal CRP is associated with BMP6 overexpression. We speculate BMP6 and hepcidin likely play different roles in the occurrence of cancer-related anemia.

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Section: Discussionmentioning

confidence: 47%

Expression of serum BMP6 and hepcidin in cancer-related anemia

Zhang

Yan

et al. 2020

Hematology

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“…Furthermore, there is an interplay between the ERK1/2 pathway and BMP/SMADs signaling that is responsible for activation of hepcidin transcription . Hepcidin expression is modulated via BMP/SMAD signaling . In particular, BMP binding to the BMP receptors that are expressed in the hepatocyte cell membrane induces activation of the receptors and phosphorylation of the cytosolic R‐SMADs (SMAD1/5/8).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, BMP binding to the BMP receptors that are expressed in the hepatocyte cell membrane induces activation of the receptors and phosphorylation of the cytosolic R‐SMADs (SMAD1/5/8). After complexing with SMAD4, the R‐SMADs move to the nucleus and activate the transcription of target genes, including HAMP . The cross‐talk between the ERK1/2 and BMP/SMADs pathways has been demonstrated, and several different mechanisms have been implied in the inhibition of BMP/SMADs signaling by ERK .…”

Section: Discussionmentioning

confidence: 99%

Gain‐of‐function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway

et al. 2019

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Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the PIEZO1 gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca 2+ influx and suppression of HAMP expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain-of-function mutants (R2456H and R2488Q), we highlight altered expression of a few genes/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca 2+ compared to WT, which was correlated to increased phosphorylation of ERK1/2, inhibition of the BMP-SMADs pathway, and suppression of HAMP transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1/2 phosphorylation, reduced the phosphorylation of ERK1/2 with the consequent increased phosphorylation of SMAD1/5/8, confirming the link between the two pathways. Another "proof of concept" for the mechanism that links PIEZO1 to HAMP regulation was obtained by mimicking PIEZO1 activation by cell Ca 2+ overload, by the Ca 2+ ionophore A23187. There was strong down-regulation of HAMP gene expression after this Ca 2+ overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron-loading anemias.

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“…One of the most important pathways involved in regulating systemic hepcidin levels in response to several stimuli is the BMP-SMAD pathway [131]. Several studies have focussed on targeting this pathway to alter hepcidin levels and normalise iron levels.…”

Section: Inhibitors Of Hepcidin Production/synthesismentioning

confidence: 99%

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

et al. 2019

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The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.

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Hepcidin and the BMP-SMAD pathway: An unexpected liaison

Cited by 91 publications

References 107 publications

Expression of serum BMP6 and hepcidin in cancer-related anemia

Expression of serum BMP6 and hepcidin in cancer-related anemia

Gain‐of‐function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

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