Increased expression of collagenase in the liver induces hepatocyte proliferation with cytoplasmic accumulation of beta-catenin in the rat.
OBJECTIVE
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.
Nishio
Toshihiro
T
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Iimuro
Yuji
Y
Nitta
Takashi
T
Harada
Nobuko
N
Yoshida
Masanori
M
Hirose
Tetsuro
T
Yamamoto
Naritaka
N
Morimoto
Taisuke
T
Brenner
David A
DA
Yamaoka
Yoshio
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004792:Enzyme Precursors / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D020781:Matrix Metalloproteinase 1; D053509:Matrix Metalloproteinase 13; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004792:Enzyme Precursors; D015534:Trans-Activators; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D004247:DNA; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D020781:Matrix Metalloproteinase 1