Increased expression of collagenase in the liver induces hepatocyte proliferation with cytoplasmic accumulation of beta-catenin in the rat.

BACKGROUND/AIMS: Since the hepatic extracellular matrix is remodeled in liver regeneration, we investigated whether increased collagenase activity in the liver can induce hepatocyte proliferation in vivo.

METHODS

To increase hepatic collagenase activity, human matrix metalloproteinase-1 was delivered to the rat liver by the recombinant adenoviral vector Ad5MMP-1.

RESULTS

Hepatic delivery of Ad5MMP-1 increased the 5-bromo-2-deoxyuridine labeling index and mitotic index in hepatocytes, causing an increase in the dry liver weight; control adenovirus, Ad5LacZ, had minimal effect. Hepatocyte proliferation started approximately 48 h after infection with Ad5MMP-1 and ended after about 2 weeks. The increase in the dry liver weight also returned to baseline after 2 weeks. Transient liver injury by Ad5MMP-1, reflected by increased aspartate and alanine aminotransferase levels, peaked around 1 week, and was associated with hepatocyte apoptosis. Collagenase-induced hepatocyte proliferation was accompanied by cytoplasmic accumulation of beta-catenin and a transient decrease in E-cadherin expression.

CONCLUSIONS

Modification of the hepatic extracellular matrix by collagenase induces transient hepatocyte proliferation in vivo, suggesting that the condition of the hepatic extracellular matrix per se plays a pivotal role in regulating hepatocyte proliferation.