Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice.
Partial hepatectomy triggers hepatocyte proliferation, hepatic matrix remodeling, and hepatocyte apoptosis, all of which are important processes in the regenerating liver. Previous studies have shown an increase in the levels of matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) after partial hepatectomy. The goal of this study was to investigate the role of MMP-9 in liver regeneration after partial hepatectomy. A 70% hepatectomy or sham laparotomy was performed in wild-type or MMP-9-deficient (MMP-9-/-) mice. Hepatic regeneration was determined by liver weight/total body weight ratios and BrdU staining, which was used to a calculate mitotic index at several times postoperatively. Cytokine and growth factor expression was evaluated by Luminex bead-based ELISA and Western blots. Finally, the effect of MMP-9 on apoptosis was measured using TUNEL and caspase expression. The MMP-9-/- animals had a delayed hepatic regenerative response when compared with wild-type controls. The MMP-9-deficient animals expressed significantly less VEGF, HGF, and TNF-alpha between days 2 and 3 post-hepatectomy. Apoptosis, as measured by TUNEL staining and caspase expression, was decreased in the MMP-9-/-. In conclusion, MMP-9 plays an important role in liver regeneration after partial hepatectomy by affecting matrix remodeling, as well as cytokine, growth factor, and caspase expression.
Olle
Eric W
EW
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0331, USA.
Ren
Xiaodan
X
McClintock
Shannon D
SD
Warner
Roscoe L
RL
Deogracias
Michael P
MP
Johnson
Kent J
KJ
Colletti
Lisa M
LM
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004792:Enzyme Precursors / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006498:Hepatectomy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D008115:Liver Regeneration / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D004792:Enzyme Precursors; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D020780:Matrix Metalloproteinase 9