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

Research output: Contribution to journalArticle

  • Stephen N. Hartland
  • Frank Murphy
  • Rebecca L. Aucott
  • Armand Abergel
  • Xiaoying Zhou
  • Julian Waung
  • Nishit Patel
  • Catherine Bradshaw
  • Jane Collins
  • Derek Mann
  • R. Christopher Benyon
  • John P. Iredale

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)966-978
Number of pages13
JournalLiver International
Issue number7
Publication statusPublished - Aug 2009


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.


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.


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.

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