Membrane-type 1 matrix metalloproteinase expression by hepatic stellate cells : its role in liver fibrosis
Membrane-type 1 matrix metalloproteinase expression by hepatic stellate cells : its role in liver fibrosis
Hepatic stellate cells (HSC) play a central role in the development of liver fibrosis, by both production of extracellular matrix proteins and through the secretion of the matrix degrading metalloproteinases, including gelatinase A. Gelatinase A is activated by a unique mechanism involving membrane - type 1 matrix metalloproteinase (MT1-MMP) and tissue inhibitor of metalloproteinase - 2 (TIMP-2) at the cell surface. It has been suggested that decreased 'activation' of gelatinase A is a possible mechanism for the progression of fibrosis. This thesis describes the synthesis and regulation of MT1-MMP by rat HSC and correlates this with gelatinase A activation. It goes on to study MT1-MMP expression in a rat model of liver fibrosis.
HSC isolated from normal human and rat liver, by Northern analysis HSC were found to express MT1-MMP mRNA. With time in culture on plastic MT1-MMP mRNA expression was increased, relative to β-actin, 6-fold and correlated temporally with the activation of gelatinase A as seen by gelatin zymography. Upregulation of MT1-MMP mRNA expression and gelatinase A activation was seen with both Concavalin A and TNF-α. Western immunoblotting confirmed MT1-MMP protein to the membrane fraction of HSC.
By ribonuclease protection assay MT1-MMP, gelatinase A and TIMP-2 mRNA were found to be upregulated, relative to normal, in cirrhotic rat liver. This correlated with increased amounts of 'activated' gelatinase A being found by gelatine zymography.
In contrary to previous ideas a link was therefore developed between the activation mechanism of gelatinase A and the development of liver fibrosis. Further studies were conducted on the association between gelatinase A and HSC proliferation in culture. By 3 independent methods either gelatinase A expression or its activity was inhibited and a significant reduction in proliferation was noted.
These data suggest that MT1-MMP, by its activation of gelatinase A, may play a role in the development of liver fibrosis.
University of Southampton
1999
Hovell, Christopher John
(1999)
Membrane-type 1 matrix metalloproteinase expression by hepatic stellate cells : its role in liver fibrosis.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Hepatic stellate cells (HSC) play a central role in the development of liver fibrosis, by both production of extracellular matrix proteins and through the secretion of the matrix degrading metalloproteinases, including gelatinase A. Gelatinase A is activated by a unique mechanism involving membrane - type 1 matrix metalloproteinase (MT1-MMP) and tissue inhibitor of metalloproteinase - 2 (TIMP-2) at the cell surface. It has been suggested that decreased 'activation' of gelatinase A is a possible mechanism for the progression of fibrosis. This thesis describes the synthesis and regulation of MT1-MMP by rat HSC and correlates this with gelatinase A activation. It goes on to study MT1-MMP expression in a rat model of liver fibrosis.
HSC isolated from normal human and rat liver, by Northern analysis HSC were found to express MT1-MMP mRNA. With time in culture on plastic MT1-MMP mRNA expression was increased, relative to β-actin, 6-fold and correlated temporally with the activation of gelatinase A as seen by gelatin zymography. Upregulation of MT1-MMP mRNA expression and gelatinase A activation was seen with both Concavalin A and TNF-α. Western immunoblotting confirmed MT1-MMP protein to the membrane fraction of HSC.
By ribonuclease protection assay MT1-MMP, gelatinase A and TIMP-2 mRNA were found to be upregulated, relative to normal, in cirrhotic rat liver. This correlated with increased amounts of 'activated' gelatinase A being found by gelatine zymography.
In contrary to previous ideas a link was therefore developed between the activation mechanism of gelatinase A and the development of liver fibrosis. Further studies were conducted on the association between gelatinase A and HSC proliferation in culture. By 3 independent methods either gelatinase A expression or its activity was inhibited and a significant reduction in proliferation was noted.
These data suggest that MT1-MMP, by its activation of gelatinase A, may play a role in the development of liver fibrosis.
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Published date: 1999
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Local EPrints ID: 464096
URI: http://eprints.soton.ac.uk/id/eprint/464096
PURE UUID: 607aac95-c2ee-4d0f-b037-189e564d5eb0
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Date deposited: 04 Jul 2022 21:03
Last modified: 04 Jul 2022 21:03
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Author:
Christopher John Hovell
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