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

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.