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

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.

• Authors: 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
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 29 Issue 7 Pg. 966-78 (Aug 2009) ISSN: 1478-3231 [Electronic] United States
• PMID: 19580633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, enzymology, pathology)
• Humans
• Liver (drug effects, enzymology, pathology)
• Liver Cirrhosis, Experimental (chemically induced, enzymology, pathology)
• Matrix Metalloproteinase 2 (metabolism)
• Mice
• Mice, Inbred C57BL
• Rats
• Recombinant Proteins (metabolism)
• Signal Transduction
• Time Factors