The University of Southampton
University of Southampton Institutional Repository

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

Active matrix metalloproteinase-2 promotes apoptosis of hepatic stellate cells via the cleavage of cellular N-cadherin
Active matrix metalloproteinase-2 promotes apoptosis of hepatic stellate cells via the cleavage of cellular N-cadherin
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.
apoptosis, hepatic stellate cell, matrix metalloproteinase, n-cadherin
1478-3223
966-978
Hartland, Stephen N.
ff4792ac-edcf-4cd5-acfa-4c233e5cf6b0
Murphy, Frank
e930f640-f880-4fc6-9f54-376a2d8aace7
Aucott, Rebecca L.
4fa5ea6f-2cd8-4d6f-813c-abdf11155aa1
Abergel, Armand
d9378187-f4d3-4455-892d-fe04ed051e21
Zhou, Xiaoying
84558a96-3129-44de-b295-869d9ee4d19f
Waung, Julian
4677968e-251e-42ef-bfe6-4bca722137ee
Patel, Nishit
881af7b6-3b2b-4be5-9491-f432df0a6877
Bradshaw, Catherine
95d27711-b910-463a-b9f0-ec4bc277ff08
Collins, Jane
be0e66f1-3036-47fa-9d7e-914c48710ba4
Mann, Derek
c715dfce-27ed-4696-8b51-5b9cc086f4b8
Benyon, R Christopher
6efa9278-56e6-47ec-9854-78afd98dd4c9
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2
Hartland, Stephen N.
ff4792ac-edcf-4cd5-acfa-4c233e5cf6b0
Murphy, Frank
e930f640-f880-4fc6-9f54-376a2d8aace7
Aucott, Rebecca L.
4fa5ea6f-2cd8-4d6f-813c-abdf11155aa1
Abergel, Armand
d9378187-f4d3-4455-892d-fe04ed051e21
Zhou, Xiaoying
84558a96-3129-44de-b295-869d9ee4d19f
Waung, Julian
4677968e-251e-42ef-bfe6-4bca722137ee
Patel, Nishit
881af7b6-3b2b-4be5-9491-f432df0a6877
Bradshaw, Catherine
95d27711-b910-463a-b9f0-ec4bc277ff08
Collins, Jane
be0e66f1-3036-47fa-9d7e-914c48710ba4
Mann, Derek
c715dfce-27ed-4696-8b51-5b9cc086f4b8
Benyon, R Christopher
6efa9278-56e6-47ec-9854-78afd98dd4c9
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2

Hartland, Stephen N., Murphy, Frank, Aucott, Rebecca L., Abergel, Armand, Zhou, Xiaoying, Waung, Julian, Patel, Nishit, Bradshaw, Catherine, Collins, Jane, Mann, Derek, Benyon, R Christopher and Iredale, John P. (2009) Active matrix metalloproteinase-2 promotes apoptosis of hepatic stellate cells via the cleavage of cellular N-cadherin. Liver International, 29 (7), 966-978. (doi:10.1111/j.1478-3231.2009.02070.x). (PMID:19580633)

Record type: Article

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.

This record has no associated files available for download.

More information

Published date: August 2009
Keywords: apoptosis, hepatic stellate cell, matrix metalloproteinase, n-cadherin

Identifiers

Local EPrints ID: 73027
URI: http://eprints.soton.ac.uk/id/eprint/73027
ISSN: 1478-3223
PURE UUID: 807636a2-d4c1-46b6-8e4d-d8a1cd4ed5fc

Catalogue record

Date deposited: 26 Feb 2010
Last modified: 13 Mar 2024 21:49

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×