Bone Morphogenetic Protein-6 Is Expressed in Nonparenchymal Liver Cells and Upregulated by Transforming Growth Factor-β1

Knittel, Thomas; Fellmer, Peter; Müller, Lars Peter; Ramadori, Giuliano

doi:10.1006/excr.1997.3504

Cited by 57 publications

(36 citation statements)

References 42 publications

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“…BMP6 expression was previously shown to be confined to nonparenchymal liver cells, namely hepatic stellate cells and Kupffer cells. 25 However, in iron-loaded livers, Bmp6 is also found in the hepatocytes, noticeably at the basolateral membrane domain as previously reported for hemojuvelin and TFR2 26 ( Figure 2C-D). This staining was not observed in Bmp6-deficient mice or with control goat IgG.…”

Section: Hfe Deficiency Promotes Liver Expression Of Bmp6supporting

confidence: 82%

BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression

Kautz

Meynard

Besson-Fournier

et al. 2009

Blood

103

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Section: Hfe Deficiency Promotes Liver Expression Of Bmp6supporting

confidence: 82%

BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression

Kautz

Meynard

Besson-Fournier

et al. 2009

Blood

103

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“…31,34,35 They are key opposing regulators of hepcidin expression. [14][15][16]21 Here we showed a predominant localization of BMP6 mRNA in the liver nonparenchymal cells, especially in SEC, and an exclusive expression of TMPRSS6 mRNA in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…40 The expression profile of BMP6 mRNA is consistent with a previous study. 31 In that study, researchers analyzed the expression levels of BMP6 mRNA in HSC, KC, and hepatocytes by Northern blot and only detected BMP6 mRNA in HSC and KC. They did not isolate the distinct population of SEC.…”

Section: Discussionmentioning

confidence: 99%

“…All of these cytokines are expressed in the liver and can induce hepcidin expression. 4,5,31 Like BMP6, these cytokines were also primarily expressed in nonparenchymal cells with the lowest level in hepatocytes (Figure1C-G). To verify the observations in isolated liver cells, we conducted in , and TGF-␤1 (G) in isolated rat liver hepatocytes (Hepat, n ϭ 5), KCs (n ϭ 7), SECs (n ϭ 4), and HSCs (n ϭ 6) were analyzed by qRT-PCR.…”

Section: Bmp6 Mrna Is Expressed Mainly In Liver Nonparenchymal Cells mentioning

confidence: 99%

“…Because BMP2, BMP4, BMP5, BMP9, and TGF-␤1 mRNA were also detected in the liver, 7,31 we next examined their mRNA levels by qRT-PCR. We detected small decreases in BMP2 and BMP9 mRNA in the ID group at day 1 ( Figure 3C) but not later ( Figure 3D-E).…”

Section: Acute Iron Deprivation Suppresses Hepcidin Expression By Decmentioning

confidence: 99%

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Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein

Zhang

Anderson

Wang

et al. 2011

Blood

110

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Recent studies demonstrate a pivotal role for bone morphogenic protein-6 (BMP6) and matriptase-2, a protein encoded by the TMPRSS6 gene, in the induction and suppression of hepatic hepcidin expression, respectively. We examined their expression profiles in the liver and showed a predominant localization of BMP6 mRNA in nonparenchymal cells and exclusive expression of TMPRSS6 mRNA in hepatocytes. In rats fed an iron-deficient (ID) diet for 24 hours, the rapid decrease of transferrin saturation from 71% to 24% (control vs ID diet) was associated with a 100-fold decrease in hepcidin mRNA compared with the corresponding controls. These results indicated a close correlation of low transferrin saturation with decreased hepcidin mRNA. The lower phosphorylated Smad1/5/8 detected in the ID rat livers suggests that the suppressed hepcidin expression results from the inhibition of BMP signaling. Quantitative realtime reverse transcription polymerase chain reaction analysis revealed no significant change in either BMP6 or TM-PRSS6 mRNA in the liver. However, an increase in matriptase-2 protein in the liver from ID rats was detected, suggesting that suppression of hepcidin expression in response to acute iron deprivation is mediated by an increase in matriptase-2 protein levels. (Blood. 2011;117(5): 1687-1699) IntroductionHepcidin is the key iron regulatory peptide hormone in the maintenance of iron homeostasis. It is secreted predominantly by hepatocytes. 1,2 Under physiologic conditions, its expression is regulated positively by body iron content through the bone morphogenic protein (BMP)-mediated signaling cascade. [3][4][5] In recent studies researchers have identified several proteins that can modulate BMP signaling and hepcidin expression directly or indirectly.BMP2, 4, 5, 6, 7, and 9 are cytokines of the BMP subfamily that belong to the transforming growth factor-␤ (TGF-␤) superfamily. 6 Each of these BMP ligands induces BMP signaling through receptor-activated Smad1, Smad5, and Smad8 (Smad1/5/8) and markedly increases hepcidin expression in hepatocytes. 7,8 BMP2,4,5,and 6 can also bind hemojuvelin (HJV), a BMP coreceptor, to enhance BMP signaling, resulting in an increase in hepcidin expression. 4,7 HJV is a glycosylphosphatidyl-inositol-linked membrane protein that is expressed in skeletal muscle, heart, and hepatocytes, and it plays a pivotal role in the induction of hepcidin expression. [9][10][11] Both homozygous or compound heterozygous mutations in the HJV gene, HFE2, in humans and disruption of both Hfe2 alleles in mice result in suppression of hepcidin expression and severe iron overload in the liver, pancreas, and heart. 10,12,13 In addition to BMPs, TGF-␤1 can also induce hepatic hepcidin expression. 5 BMP6 mRNA, but no other BMP mRNA, is downregulated by chronic iron depletion and up-regulated by iron loading. 3 Knockdown of the BMP6 gene in mice causes suppression of hepatic hepcidin expression. 3,14,15 These observations implicate BMP6 as a critical player in the iron-sensitive induction of hepcidin expr...

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Expression of bone morphogenetic protein 6 in normal mammary tissue and breast cancer cell lines and its regulation by epidermal growth factor

Clement

Sänger²,

Höffken

1999

Int. J. Cancer

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Bone Morphogenetic Protein-6 Is Expressed in Nonparenchymal Liver Cells and Upregulated by Transforming Growth Factor-β1

Cited by 57 publications

References 42 publications

BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression

BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression

Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein

Expression of bone morphogenetic protein 6 in normal mammary tissue and breast cancer cell lines and its regulation by epidermal growth factor

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