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Loss of matrix metalloproteinase-2 amplifies murine toxin-induced liver fibrosis by upregulating collagen I expression.

Abstract：

BACKGROUND AND AIMS: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.

journal_name

Dig Dis Sci

journal_title

Digestive diseases and sciences

authors

Radbill BD,Gupta R,Ramirez MC,DiFeo A,Martignetti JA,Alvarez CE,Friedman SL,Narla G,Vrabie R,Bowles R,Saiman Y,Bansal MB

doi

10.1007/s10620-010-1296-0

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

406-16

issue

eissn

0163-2116

issn

1573-2568

journal_volume

pub_type

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Loss of matrix metalloproteinase-2 amplifies murine toxin-induced liver fibrosis by upregulating collagen I expression.