Digestive Diseases and Sciences

, Volume 56, Issue 2, pp 406–416

Loss of Matrix Metalloproteinase-2 Amplifies Murine Toxin-Induced Liver Fibrosis by Upregulating Collagen I Expression

  • Brian D. Radbill
  • Ritu Gupta
  • Maria Celeste M. Ramirez
  • Analisa DiFeo
  • John A. Martignetti
  • Carlos E. Alvarez
  • Scott L. Friedman
  • Goutham Narla
  • Raluca Vrabie
  • Robert Bowles
  • Yedidya Saiman
  • Meena B. Bansal
Original Article

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 CCl4 liver injury and explored the effect of MMP-2 deficiency and overexpression on collagen I expression.

Methods

Following chronic CCl4 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.

Keywords

Cirrhosis Fibrogenesis Type I collagen Hepatic stellate cell Matrix metalloproteinase-2 

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Brian D. Radbill
    • 1
  • Ritu Gupta
    • 2
  • Maria Celeste M. Ramirez
    • 3
  • Analisa DiFeo
    • 3
  • John A. Martignetti
    • 3
  • Carlos E. Alvarez
    • 2
  • Scott L. Friedman
    • 2
  • Goutham Narla
    • 3
  • Raluca Vrabie
    • 2
  • Robert Bowles
    • 2
  • Yedidya Saiman
    • 2
  • Meena B. Bansal
    • 2
  1. 1.Division of Nephrology, Department of MedicineMount Sinai School of MedicineNew YorkUSA
  2. 2.Division of Liver Diseases, Department of MedicineMount Sinai School of MedicineNew YorkUSA
  3. 3.Departments of Medicine and Genetics and Genomic SciencesMount Sinai School of MedicineNew YorkUSA

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