Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge

Abstract

Lack of either bone morphogenetic protein 6 (BMP6) or the BMP coreceptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin insufficiency, hepatic iron loading, and extrahepatic iron accumulation in males. This is consistent with the current views that HJV is a coreceptor for BMP6 in hepatocytes. To determine whether BMP6 and HJV may also signal to hepcidin independently of each other, we intercrossed and mice and compared the phenotype of animals of the F2 progeny. Loss of Bmp6 further repressed Smad signaling and hepcidin expression in the liver of mice of both sexes, and led to iron accumulation in the pancreas and the heart of females. These data suggest that, in females, Bmp6 can provide a signal adequate to maintain hepcidin to a level sufficient to avoid extrahepatic iron loading. We also examined the impact of Bmp6 and/or Hjv deletion on the regulation of hepcidin by inflammation. Our data show that lack of 1 or both molecules does not prevent induction of hepcidin by lipopolysaccharide (LPS). However, BMP/Smad signaling in unchallenged animals is determinant for the level of hepcidin reached after stimulation, which is consistent with a synergy between interleukin 6/STAT3 and BMP/SMAD signaling in regulating hepcidin during inflammation.

H2O2 induces oxidative stress damage through the BMP‐6/SMAD/hepcidin axis

“…BMP‐6 gene knockout mice would exhibit obvious Hepcidin deficiency, which would lead to the accumulation of retinal iron. It has been found that an increase in serum iron can improve oxidative stress markers in mouse photoreceptors and significantly increase the oxidative stress in retina (Latour et al, ). In hepatocyte cell lines, heparin can effectively inhibit hepcidin expression by inhibiting phosphorylation of the SMAD1/5/8 proteins induced by BMPs (Poli, Asperti, Ruzzenenti, Naggi, & Arosio, ).…”

Iron, erythropoietin, and inflammation regulate hepcidin in Bmp2‐deficient mice, but serum iron fails to induce hepcidin in Bmp6‐deficient mice

“…However, erythropoietin retains the ability to suppress hepcidin in Bmp6 −/− mice . In a similar vein, inflammation induces SMAD1/5/8 phosphorylation in hepatocytes, but retains the ability to stimulate hepcidin in Bmp6 −/− mice . These data also suggest the possibility that erythropoietic drive and/or inflammation may also regulate the production of or response to another BMP family ligand to control hepcidin production.…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…In hepatocytes, it has been well‐documented that inflammation induces hepcidin gene expression via the interleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 (STAT3) pathway, via iron sensing through the transferrin receptor 2 (TfR2)/human hemochromatosis protein (HFE), and the bone morphogenetic protein (BMP)/hemojuvelin (HJV)/SMAD (a small mothers of decapentaplegic protein) pathways, and downregulated by erythroferrone (ERFE) ‐dependent and ‐independent mechanisms . Recent studies have also demonstrated that hepcidin expression can be upregulated by progesterone and mifepristone, two steroid hormones, through cell surface protein progesterone receptor membrane component‐1, transforming growth factor β1, SMAD1/5/8‐independent signaling by activin B, oxidases such as NADPH‐dependent oxidase 4 or artificially overexpressed urate oxidase (UOX), IL‐1β via inducing CCAAT enhancer‐binding protein δ (C/EBPδ) expression, peroxiredoxin‐2 which is a supporter for STAT3 transcriptional activity, fibroblast growth factor‐encoding gene, and downregulated by the immunophilin FKBP12 (FK506‐binding protein 1A) via binding with BMP type I receptor ALK2, cystathionine β‐synthase, TfR1, and matriptase‐2 …”