The role of matrix metalloproteinase-2 in liver fibrosis
The role of matrix metalloproteinase-2 in liver fibrosis
Hypothesis:MMP-2 promotes fibrosis by increasing HSC proliferation in injured liver, when HSC receive survival/proliferation signals from other liver cells, but promotes HSC apoptosis during recovery when such signals are terminated due to removal of liver injury. During recovery from liver fibrosis, MMP-2 is required for degradation of the accumulated collagen.
Aims: To determine a) the distribution of MMP-2 in liver fibrosis and the role of MMP-2, in mediating HSC proliferation and apoptosis b) the role of matrix turnover in regulating MMP-2 effects c) the mechanisms involved in regulating MMP-2 activity d) the phenotype of experimental hepatic fibrosis in MMP-2-/- mice liver compared with wild type (WT) controls.
Conclusion: MMP-2 shows differential effects on HSC being proliferative or apoptotic depending on its concentration. This is consistent with a model that during fibrogenesis when MMP-2 activity is restrained by TIMPs, limited collagen degradation by MMP-2 contributes to expansion of HSC numbers possibly by generating ligands which activates MAPK and induces proliferation. During resolution of fibrosis when TIMP expression decreases, unrestrained MMP-2 degradation of matrix might contribute to the observed apoptosis of HSC. Although previous studies have concentrated on TIMPS, I show that RECK has a role in both MMP-2 secretion and regulation of MMP-2 activity in HSC. As MMP-2 has been implicated in HSC proliferation, RECK may regulate this important aspect of the fibrogenic response. Upregulation of MMP-9 compensates for the lack of MMP-2 in our knockout model resulting in the absence of a phenotypic difference.
University of Southampton
2007
Jamil, Aqeel
(2007)
The role of matrix metalloproteinase-2 in liver fibrosis.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Hypothesis:MMP-2 promotes fibrosis by increasing HSC proliferation in injured liver, when HSC receive survival/proliferation signals from other liver cells, but promotes HSC apoptosis during recovery when such signals are terminated due to removal of liver injury. During recovery from liver fibrosis, MMP-2 is required for degradation of the accumulated collagen.
Aims: To determine a) the distribution of MMP-2 in liver fibrosis and the role of MMP-2, in mediating HSC proliferation and apoptosis b) the role of matrix turnover in regulating MMP-2 effects c) the mechanisms involved in regulating MMP-2 activity d) the phenotype of experimental hepatic fibrosis in MMP-2-/- mice liver compared with wild type (WT) controls.
Conclusion: MMP-2 shows differential effects on HSC being proliferative or apoptotic depending on its concentration. This is consistent with a model that during fibrogenesis when MMP-2 activity is restrained by TIMPs, limited collagen degradation by MMP-2 contributes to expansion of HSC numbers possibly by generating ligands which activates MAPK and induces proliferation. During resolution of fibrosis when TIMP expression decreases, unrestrained MMP-2 degradation of matrix might contribute to the observed apoptosis of HSC. Although previous studies have concentrated on TIMPS, I show that RECK has a role in both MMP-2 secretion and regulation of MMP-2 activity in HSC. As MMP-2 has been implicated in HSC proliferation, RECK may regulate this important aspect of the fibrogenic response. Upregulation of MMP-9 compensates for the lack of MMP-2 in our knockout model resulting in the absence of a phenotypic difference.
This record has no associated files available for download.
More information
Published date: 2007
Identifiers
Local EPrints ID: 466438
URI: http://eprints.soton.ac.uk/id/eprint/466438
PURE UUID: 8bb1a044-99d4-4334-9ce1-ef905361dd61
Catalogue record
Date deposited: 05 Jul 2022 05:16
Last modified: 05 Jul 2022 05:16
Export record
Contributors
Author:
Aqeel Jamil
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