Role of Matrix Metalloproteinase-2 in Liver Fibrosis

Summary

Principal Investigator: Meena B Bansal
Abstract: [unreadable] DESCRIPTION (provided by applicant): [unreadable] Regardless of the etiology of chronic liver injury, the final common pathway for liver injury and failure is fibrosis. Fibrosis with subsequent complications of portal hypertension results in the death of patients awaiting liver transplantation. Given the severe shortage of donor organs, there is an urgent need to understand the molecular basis of hepatic fibrosis in order to develop effective anti-fibrotic strategies. Liver fibrosis is characterized by activation of hepatic stellate cells which orchestrate a shift in the normal extracellular (ECM) comprised of mostly collagen type IV to a high-density interstitial matrix composed of predominantly type I collagen. Therefore, potential antifibrotic strategies include reduction in type I collagen synthesis, stimulation of matrix degradation, and/or promotion of stellate cell apoptosis. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase, produced by activated hepatic stellate cells (HSCs), is increased in patients with chronic hepatitis and cirrhosis, suggesting a causative role in the fibrotic process. MMP-2 is also capable of acting as a type I collagenase, is upregulated in both animal and human hepatic fibrosis, is increased during resolution of fibrosis, and is associated with stellate cell apoptosis, we hypothesize that MMP-2 may play a protective rather than deleterious role in chronic liver injury. MMP-2 -/- mice offer an opportunity to clarify the physiologic role of MMP-2 in liver fibrosis. This study will employ the use of CCI4-induced chronic liver injury model to determine whether MMP-2 is important in attenuating liver fibrosis by directly reducing collagen I expression. Its role in acting as an interstitial collagenase will be assessed by 1) comparing the rate of spontaneous resolution of fibrosis between MMP-2 -/- and MMP-2 +/+ mice and 2) quantifying interstitial collagenase activity in both cohorts. In addition, a potential role for MMP-2 in promoting stellate cell apoptosis will be examined in both in vivo and in vitro models. Findings from these investigations may lead to novel approaches to the treatment of chronic fibrosing liver disease. [unreadable] [unreadable]
Funding Period: 2006-09-05 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. pmc Activated hepatic stellate cells upregulate transcription of ecto-5'-nucleotidase/CD73 via specific SP1 and SMAD promoter elements
    Michel Fausther
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Am J Physiol Gastrointest Liver Physiol 303:G904-14. 2012
  2. pmc CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway
    Yedidya Saiman
    Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Rm 11 70, Box 1123, New York, NY 10029
    Am J Physiol Gastrointest Liver Physiol 305:G375-82. 2013
  3. pmc Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation
    Feng Hong
    Mount Sinai School of Medicine, New York, NY 10029, USA
    Hepatology 49:2055-67. 2009
  4. pmc Loss of matrix metalloproteinase-2 amplifies murine toxin-induced liver fibrosis by upregulating collagen I expression
    BRIAN D RADBILL
    Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Dig Dis Sci 56:406-16. 2011
  5. pmc Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis
    Ana C Tuyama
    Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Hepatology 52:612-22. 2010
  6. pmc X4 Human immunodeficiency virus type 1 gp120 promotes human hepatic stellate cell activation and collagen I expression through interactions with CXCR4
    Feng Hong
    Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America
    PLoS ONE 7:e33659. 2012

Scientific Experts

  • Meena B Bansal
  • Yedidya Saiman
  • Feng Hong
  • Michel Fausther
  • Jonathan A Dranoff
  • Scott L Friedman
  • BRIAN D RADBILL
  • Ritu Agarwal
  • Arevik Mosoian
  • Ana C Tuyama
  • Ahmed El-Shamy
  • Dashawn A Hickman
  • Nina Sheung
  • Chuanping Si
  • Robert Bowles
  • Carlos E Alvarez
  • Goutham Narla
  • John A Martignetti
  • Raluca Vrabie
  • Maria Celeste M Ramirez
  • Ritu Gupta
  • Analisa Difeo
  • Chuansheng Wang
  • Ping Chen
  • Benjamin K Chen
  • Derya Ozkok
  • Mary E Klotman
  • Myron Schwartz
  • M Isabel Fiel
  • Ana Tuyama
  • Andrea Branch
  • Alison D Schecter
  • Johnny Loke
  • Jose Walewski
  • Ting Fang Lee
  • Xin Cheng
  • Anita Garg

Detail Information

Publications6

  1. pmc Activated hepatic stellate cells upregulate transcription of ecto-5'-nucleotidase/CD73 via specific SP1 and SMAD promoter elements
    Michel Fausther
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Am J Physiol Gastrointest Liver Physiol 303:G904-14. 2012
    ..The ecto-5'-nucleotidase/CD73 enzyme is a novel cellular marker of activated liver myofibroblasts in vivo and in vitro and thus represents a promising molecular target for antifibrotic therapies in liver diseases...
  2. pmc CXCL12 induces hepatic stellate cell contraction through a calcium-independent pathway
    Yedidya Saiman
    Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Rm 11 70, Box 1123, New York, NY 10029
    Am J Physiol Gastrointest Liver Physiol 305:G375-82. 2013
    ....
  3. pmc Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation
    Feng Hong
    Mount Sinai School of Medicine, New York, NY 10029, USA
    Hepatology 49:2055-67. 2009
    ..Inhibitor studies suggest that SDF-1alpha/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation...
  4. pmc Loss of matrix metalloproteinase-2 amplifies murine toxin-induced liver fibrosis by upregulating collagen I expression
    BRIAN D RADBILL
    Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Dig Dis Sci 56:406-16. 2011
    ..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...
  5. pmc Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis
    Ana C Tuyama
    Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Hepatology 52:612-22. 2010
    ..Furthermore, infected LX-2 cells were capable of transferring GFP-expressing virus to T lymphocytes in a coculture system...
  6. pmc X4 Human immunodeficiency virus type 1 gp120 promotes human hepatic stellate cell activation and collagen I expression through interactions with CXCR4
    Feng Hong
    Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America
    PLoS ONE 7:e33659. 2012
    ..We therefore examined the in vitro impact of X4 gp120 on HSC activation, collagen I expression, and underlying signaling pathways and examined the in vivo expression of gp120 in HIV/HCV coinfected livers...