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

Radbill, Brian; Gupta, Ritu; Ramirez, Maria; DiFeo, Analisa; Martignetti, John; Alvarez, Carlos; Friedman, Scott; Narla, Goutham; Vrabie, Raluca; Bowles, Robert; Saiman, Yedidya; Bansal, Meena; Radbill, Brian D; Ramirez, Maria Celeste M; Martignetti, John A; Alvarez, Carlos E; Friedman, Scott L; Bansal, Meena B
February 2011
Digestive Diseases & Sciences;Feb2011, Vol. 56 Issue 2, p406
Academic Journal
journal article
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.


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