Gene targeting in hemostasis. Hepsin

Hepsin is a type II transmembrane serine protease abundantly expressed on t he surface of hepatocytes. Biochemical studies have shown that hepsin is an enzyme of 51 kDa with the trypsin-like substrate specificity. Several in v itro studies have suggested that hepsin may play a role in blood coagulatio n, hepatocyte growth, and fertilization. To determine the functional import ance of hepsin, hepsin-deficient mice were generated by homologous recombin ation. Homozygous hepsin-/- mice were viable and fertile, and grew normally . When analyzed in hemostasis assays, such as tail bleeding time and plasma clotting times, and in vivo modes, such as disseminated intravascular coag ulation, septic shock, and acute liver regeneration, hepsin-/- mice had sim ilar phenotypes as wild-type controls. Liver weight and serum concentration s of liver-derived proteins or enzymes were also similar in hepsin-/- and w ild-type mice. No abnormalities were identified in major organs in hepsin-/ - mice in histological examinations. These results indicate that hepsin is not an essential enzyme for normal hemostasis, embryogenesis, and maintenan ce of normal liver function. Unexpectedly, serum concentrations of bone-der ived alkaline phosphatase were approximately two-fold higher in both male a nd female hepsin-/- mice than those in wild-type controls. The underlying m echanism for this phenotype and long-term effects of hepsin deficiency rema in to be determined.