Loss of matrix metalloproteinase-2 amplifies murine toxin-induced liver fibrosis by upregulating collagen I expression.
OBJECTIVE
Matrix metalloproteinase-2 (MMP-2), a type IV collagenase secreted by activated hepatic stellate cells (HSCs), is upregulated in chronic liver disease and is considered a profibrotic mediator due to its proliferative effect on cultured HSCs and ability to degrade normal liver matrix. Although associative studies and cell culture findings suggest that MMP-2 promotes hepatic fibrogenesis, no in vivo model has definitively established a pathologic role for MMP-2 in the development and progression of liver fibrosis. We therefore examined the impact of MMP-2 deficiency on liver fibrosis development during chronic CCl(4) liver injury and explored the effect of MMP-2 deficiency and overexpression on collagen I expression.


METHODS
Following chronic CCl(4) administration, liver fibrosis was analyzed using Sirius Red staining with quantitative morphometry and real-time polymerase chain reaction (PCR) in MMP-2-/- mice and age-matched MMP-2+/+ controls. These studies were complemented by analyses of cultured human stellate cells.


RESULTS
MMP-2-/- mice demonstrated an almost twofold increase in fibrosis which was not secondary to significant differences in hepatocellular injury, HSC activation or type I collagenase activity; however, type I collagen messenger RNA (mRNA) expression was increased threefold in the MMP-2-/- group by real-time PCR. Furthermore, targeted reduction of MMP-2 in cultured HSCs using RNA interference significantly increased collagen I mRNA and protein, while overexpression of MMP-2 resulted in decreased collagen I mRNA.


CONCLUSIONS
These findings suggest that increased MMP-2 during the progression of liver fibrosis may be an important mechanism for inhibiting type I collagen synthesis by activated HSCs, thereby providing a protective rather than pathologic role.
Radbill
Brian D
BD
Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Gupta
Ritu
R
Ramirez
Maria Celeste M
MC
DiFeo
Analisa
A
Martignetti
John A
JA
Alvarez
Carlos E
CE
Friedman
Scott L
SL
Narla
Goutham
G
Vrabie
Raluca
R
Bowles
Robert
R
Saiman
Yedidya
Y
Bansal
Meena B
MB
D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055166:Hepatic Stellate Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
D024042:Collagen Type I; D012313:RNA; D002251:Carbon Tetrachloride; D020778:Matrix Metalloproteinase 2