Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

Pagani, Alessia; Pettinato, Mariateresa; Colucci, Silvia; Dulja, Alessandro; Rauner, Martina; Nai, Antonella; Camaschella, Clara; Altamura, Sandro; Muckenthaler, Martina U.; Silvestri, Laura

doi:10.3324/haematol.2019.241984

Cited by 10 publications

(10 citation statements)

References 16 publications

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“…134 Consistently, Bmp2 was not induced in iron-loaded Bmp6, Hfe, Tfr2 and Hjv KO mice, in contrast to Bmp6, which is typically upregulated in hemochromatosis mouse models. 134,140 Much in agreement with all the above observations, Bmp6 ablation completely prevents or blunts hepcidin induction by liver iron stores, 122 but deletion of Bmp2 only very mildly reduces hepcidin induction by this type of stimulus. 136 Another line of research investigates how HH-associated proteins, HFE, TFR2 and HJV that act predominantly in hepatocytes, 121,124,141 intersect in vivo with functions of BMP6 and BMP2.…”

Section: Paracrine Mechanisms Involved In Hepcidin Regulation In Thsupporting

confidence: 72%

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Cell‐type‐specific insights into iron regulatory processes

Mleczko-Sanecka

Silvestri

2020

American J Hematol

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Despite its essential role in many biological processes, iron is toxic when in excess due to its propensity to generate reactive oxygen species. To prevent diseases associated with iron deficiency or iron loading, iron homeostasis must be tightly controlled. Intracellular iron content is regulated by the Iron Regulatory Element‐Iron Regulatory Protein (IRE‐IRP) system, whereas systemic iron availability is adjusted to body iron needs chiefly by the hepcidin‐ferroportin (FPN) axis. Here, we aimed to review advances in the field that shed light on cell‐type‐specific regulatory mechanisms that control or modify systemic and local iron balance, and how shifts in cellular iron levels may affect specialized cell functions.

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Section: Paracrine Mechanisms Involved In Hepcidin Regulation In Thsupporting

confidence: 72%

“…134 Furthermore, BMP2 administration was recently shown to efficiently induce hepcidin in HH mice. 140 Altogether, these data suggest that both BMPs act partially independent of the hemochromatosis proteins.…”

Section: Paracrine Mechanisms Involved In Hepcidin Regulation In Thmentioning

confidence: 87%

Cell‐type‐specific insights into iron regulatory processes

Mleczko-Sanecka

Silvestri

2020

American J Hematol

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“…(47) Along these lines, ALK5 inhibition may be beneficial for patients with the iron overload disorder hereditary hemochromatosis. In support of this idea, we recently showed that acute BMP2 treatment induces hepcidin expression in disease models of hereditary hemochromatosis, (48) a common disorder characterized by primary iron overload due to inappropriately low hepcidin levels. (49) Future experiments will have to assess whether drugs interfering with TGFβ-mediated BMP2 regulation may be applicable for the treatment of iron overload diseases.…”

Section: Discussionmentioning

confidence: 81%

Liver Sinusoidal Endothelial Cells Suppress Bone Morphogenetic Protein 2 Production in Response to TGFβ Pathway Activation

et al. 2021

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Background & Aims:TGFβ/BMP signalling in the liver plays a critical role in liver disease. Growth factors, such as BMP2, BMP6 and TGFβ1, are released from liver sinusoidal endothelial cells (LSECs) and signal in a paracrine manner to hepatocytes and hepatic stellate cells to control systemic iron homeostasis and fibrotic processes, respectively. The misregulation of the TGFβ/BMP pathway affects expression of the iron-regulated hormone hepcidin causing frequent iron overload and deficiency diseases. However, whether LSEC-secreted factors can act in an autocrine manner to maintain liver homeostasis was not addressed so far.

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“…136 Indeed, whereas Bmp6 mRNA is appropriately induced by iron overload in hemochromatosis mouse models, Bmp2 mRNA is not increased in Bmp6, Hjv, Tfr2, or Hfe-deficient mice despite iron overload. 71,74,86,161,162 These data suggest that Bmp2 regulation by iron depends on BMP6 and hemochromatosis proteins, whereas Bmp6 regulation does not. Notably, the lack of validated antibodies to detect endogenous BMP6 protein expression has limited the ability to assess whether there is additional regulation of BMP production or activity by iron at the posttranscriptional level.…”

Section: Tissue Iron Sensingmentioning

confidence: 86%

“…Indeed, BMP6 and BMP2 treatment still induce hepcidin in HJVdeficient or knockout hepatocyte cultures, albeit to a lesser extent than in the presence of HJV. 39,162,191 Moreover, knockout of Bmp6 further suppresses hepcidin in Hjv knockout mice, suggesting that BMP6 can still induce hepcidin to some extent in the absence of HJV in vivo. 112 Additional key unanswered questions are: how does HJV facilitate BMP-SMAD signal transduction, and what is the complete nature of the BMP signaling complex that regulates hepcidin and iron homeostasis in vivo?…”

Section: Composition Of the Bmp Ligand-receptor Complex And Contribution Of Accessory Proteins To Hepcidin Regulationmentioning

confidence: 99%

Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions

Fisher

Babitt

2021

Developmental Dynamics

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Iron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)‐SMAD pathway, which controls hepcidin transcription. Genetic disorders of iron overload and iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP‐SMAD and hepcidin regulatory response to iron. However, the precise molecular mechanisms by which serum and tissue iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses iron levels to regulate BMP‐SMAD signaling and thereby hepcidin expression to control systemic iron homeostasis.

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Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

Cited by 10 publications

References 16 publications

Cell‐type‐specific insights into iron regulatory processes

Cell‐type‐specific insights into iron regulatory processes

Liver Sinusoidal Endothelial Cells Suppress Bone Morphogenetic Protein 2 Production in Response to TGFβ Pathway Activation

Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions

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