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
966-978
Hartland, Stephen N.
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Murphy, Frank
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Aucott, Rebecca L.
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Abergel, Armand
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Zhou, Xiaoying
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Waung, Julian
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Patel, Nishit
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Bradshaw, Catherine
95d27711-b910-463a-b9f0-ec4bc277ff08
Collins, Jane
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Mann, Derek
c715dfce-27ed-4696-8b51-5b9cc086f4b8
Benyon, R Christopher
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Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2
August 2009
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), .
(doi:10.1111/j.1478-3231.2009.02070.x).
(PMID:19580633)
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.
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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
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Date deposited: 26 Feb 2010
Last modified: 13 Mar 2024 21:49
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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:
Derek Mann
Author:
R Christopher Benyon
Author:
John P. Iredale
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