Active matrix metalloproteinase-2 promotes apoptosis of hepatic stellate cells via the cleavage of cellular N-cadherin

Liver Int. 2009 Aug;29(7):966-78. doi: 10.1111/j.1478-3231.2009.02070.x.

Abstract

Background and aims: Hepatic stellate cells (HSC) are known to synthesise excess matrix that characterises liver fibrosis and cirrhosis. Activated HSC express the matrix-degrading matrix metalloproteinase enzymes (MMPs) and their tissue inhibitors (TIMPs). During spontaneous recovery from experimental liver fibrosis, the expression of TIMP-1 declines and hepatic collagenolytic activity increases. This is accompanied by HSC apoptosis. In this study, we examine a potential mechanism whereby MMP activity might induce HSC apoptosis by cleaving N-cadherin at the cell surface.

Results: N-cadherin expression was upregulated in human HSC during activation in culture. Addition of function-blocking antibodies or a peptide targeting the extracellular domain of N-cadherin, to cultured HSC, promoted apoptosis. During apoptosis, there was cleavage of N-cadherin into 20-100 kDa fragments. MMP-2 became activated early during HSC apoptosis and directly cleaved N-cadherin in vitro. Addition of activated MMP-2 to HSCs in culture resulted in enhanced apoptosis and loss of N-cadherin.

Conclusions: Together, these studies identify a role for both N-cadherin and MMP-2 in mediating HSC apoptosis, where N-cadherin works to provide a cell survival stimulus and MMP-2 promotes HSC apoptosis concomitant with N-cadherin degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Apoptosis* / drug effects
  • Cadherins / metabolism*
  • Carbon Tetrachloride
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Cycloheximide / pharmacology
  • Enzyme Activation
  • Gliotoxin / pharmacology
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / enzymology*
  • Hepatic Stellate Cells / pathology
  • Humans
  • Liver / drug effects
  • Liver / enzymology*
  • Liver / pathology
  • Liver Cirrhosis, Experimental / chemically induced
  • Liver Cirrhosis, Experimental / enzymology*
  • Liver Cirrhosis, Experimental / pathology
  • Matrix Metalloproteinase 2 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Time Factors

Substances

  • Antigens, CD
  • CDH2 protein, human
  • Cadherins
  • Cdh2 protein, mouse
  • Recombinant Proteins
  • Gliotoxin
  • Cycloheximide
  • Carbon Tetrachloride
  • Caspase 3
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse