Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6

Br J Haematol. 2009 Nov;147(4):571-81. doi: 10.1111/j.1365-2141.2009.07873.x. Epub 2009 Sep 8.


Hepcidin, the master regulator of enteric iron absorption, is controlled by the opposing effects of pathways activated in response to iron excess or iron attenuation. Iron excess is regulated through a pathway involving the cell surface receptor hemojuvelin (HFE2) that stimulates expression of the hepcidin encoding gene (HAMP). Iron attenuation is countered through a pathway involving the hepatocyte-specific plasma membrane protease matriptase-2 encoded by TMPRSS6, leading to suppression of HAMP expression. The non-redundant function of hemojuvelin and matriptase-2 has been deduced from the phenotype imparted by mutations of HFE2 and TMPRSS6, which cause iron excess and iron deficiency respectively. Hemojuvelin is positioned to be the ideal substrate for matriptase-2. To examine the relationship between hemojuvelin and matriptase-2 in vivo, we crossed mice lacking the protease domain of matriptase-2 with mice lacking hemojuvelin. Mice lacking functional matriptase-2 and hemojuvelin exhibited low Hamp (Hamp1) expression, high serum and liver iron, and high transferrin saturation. Surprisingly, the double mutant mice also exhibited lower levels of iron in the heart compared to hemojuvelin-deficient mice, demonstrating a possible cardioprotective effect resulting from the loss of matriptase-2. This phenotype is consistent with hemojuvelin being a major substrate for matriptase-2/TMPRSS6 protease activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / biosynthesis
  • Antimicrobial Cationic Peptides / genetics*
  • Bone Morphogenetic Proteins / pharmacology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • GPI-Linked Proteins
  • Hemochromatosis Protein
  • Hepatocytes / drug effects
  • Hepcidins
  • Interleukin-6 / pharmacology
  • Iron / analysis
  • Iron / blood
  • Iron Overload / genetics*
  • Iron Overload / physiopathology
  • Iron, Dietary / pharmacology
  • Membrane Proteins / deficiency*
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • RNA, Messenger / genetics
  • Serine Endopeptidases / deficiency*
  • Serine Endopeptidases / physiology
  • Transferrin / metabolism
  • Up-Regulation / drug effects


  • Antimicrobial Cationic Peptides
  • Bone Morphogenetic Proteins
  • GPI-Linked Proteins
  • HJV protein, mouse
  • Hamp protein, mouse
  • Hemochromatosis Protein
  • Hepcidins
  • Interleukin-6
  • Iron, Dietary
  • Membrane Proteins
  • RNA, Messenger
  • Transferrin
  • Iron
  • Serine Endopeptidases
  • matriptase 2