Apoptosis of hepatic stellate cells (HSC) has previously been shown to occur during spontaneous resolution of experimental liver fibrosis. TIMP-1 has also been shown to have a key role because of its ability to inhibit apoptosis of HSC via matrix metalloproteinase (MMP) inhibition. This has led to further study of novel substrates for MMPs that might impact on HSC survival. N-Cadherin is known to mediate cell-cell contacts in fibroblasts. In this study we demonstrate that N-Cadherin is expressed by activated rat HSC. Furthermore, during apoptosis of HSC, the N-Cadherin is cleaved into smaller fragments. Apoptosis of HSC may be inhibited by TIMP-1. This is associated with reduced fragmentation of N-Cadherin. N-Cadherin may have an important role in supporting HSC survival while N-Cadherin cleavage may play a part in promoting HSC apoptosis in recovery from liver fibrosis

Arthur, Michael J.P.

Benyon, R. Christopher

Collins, Jane

Iredale, John P.

Mann, Derek

Murphy, Frank

Nagase, Hideaki

Waung, Julian

English

PubMed

Southampton (e-Prints Soton)

BioMed CentralComparative HepatologyssOpen AcceProceedingsN-Cadherin cleavage during activated hepatic stellate cell apoptosis is inhibited by tissue inhibitor of metalloproteinase-1Frank Murphy*1, Julian Waung1, Jane Collins2, Michael JP Arthur1, Hideaki Nagase3, Derek Mann1, R Christopher Benyon1 and John P Iredale1Address: 1Liver group, Division of Infection, Inflammation and Repair, Southampton University, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK, 2Mucosal Immunology, Southampton University, Tremona Road, Southampton, UK and 3The Kennedy Institute, Imperial College, 1 Aspenlea Road, London W6, UKEmail: Frank Murphy* - frm105@hotmail.com; Julian Waung - jw1197@soton.ac.uk; Jane Collins - jec3@soton.ac.uk; Michael JP Arthur - mja1@soton.ac.uk; Hideaki Nagase - h.nagase@ic.ac.uk; Derek Mann - dam@soton.ac.uk; R Christopher Benyon - rcb@soton.ac.uk; John P Iredale - J.P.Iredale@soton.ac.uk* Corresponding author    AbstractApoptosis of hepatic stellate cells (HSC) has previously been shown to occur during spontaneousresolution of experimental liver fibrosis. TIMP-1 has also been shown to have a key role becauseof its ability to inhibit apoptosis of HSC via matrix metalloproteinase (MMP) inhibition. This has ledto further study of novel substrates for MMPs that might impact on HSC survival. N-Cadherin isknown to mediate cell-cell contacts in fibroblasts. In this study we demonstrate that N-Cadherinis expressed by activated rat HSC. Furthermore, during apoptosis of HSC, the N-Cadherin iscleaved into smaller fragments. Apoptosis of HSC may be inhibited by TIMP-1. This is associatedwith reduced fragmentation of N-Cadherin. N-Cadherin may have an important role in supportingHSC survival while N-Cadherin cleavage may play a part in promoting HSC apoptosis in recoveryfrom liver fibrosis.IntroductionThe activated hepatic stellate cell plays a key role in liverfibrosis [1]. During spontaneous recovery from experi-mental liver fibrosis loss of activated hepatic stellate cells(HSCs) has been demonstrated to be through apoptosisor programmed cell death [2,3]. This has highlighted con-trol of HSC apoptosis for further investigation. Duringspontaneous resolution of experimental liver fibrosisthere is a change in the balance between matrix metallo-proteinase (MMP) activity and their endogenous inhibi-tor TIMP-1. This change favours matrix degradation.During resolution of fibrosis there is a great reduction inTIMP-1 expression. Correlating with this event there is afall in the numbers of activated HSCs. This observationwas recently studied in depth in vitro. TIMP-1 reducedapoptosis of culture activated HSC in a dose dependentmanner. Inhibition of HSC apoptosis by TIMP-1 has pre-viously been shown to be due to its action of MMP inhi-bition [4]. This has led to the further study of potentialMMPs and MMP substrates on the cell surface that mightimpact on HSC survival.N-Cadherin, which mediates cell to cell contact, isexpressed in activated HSC. It has been shown to signalvia the beta-catenin pathway. Disruption of this interac-tion with blocking antibodies has been shown to promoteapoptosis in melanoma cells [5]. Furthermore, MMPinhibitors including TIMPs have been demonstrated tofrom 11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other CellsTucson, Arizona, USA, 25–29 August, 2002Published: 14 January 2004Comparative Hepatology 2004, 3(Suppl 1):S8<supplement> <title> <p>11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells</p> </title> </supplement>This article is available from: http://www.comparative-hepatology.com/content/3/S1/S8Page 1 of 3(page number not for citation purposes)Comparative Hepatology 2004, 3 http://www.comparative-hepatology.com/content/3/S1/S8promote fibroblast adhesion through stabilisation offocal adhesion contacts and up regulation of Cadherinfunction in vitro [6]. We studied the fate of N-Cadherin inHSC during apoptosis induced by cycloheximide or glio-toxin. We have demonstrated that activated rat HSCexpress intact 135 kDa N-Cadherin and that during apop-tosis of these cells the N-Cadherin is degraded intosmaller fragments. We have also demonstrated that TIMP-1 is able to reduce apoptosis of activated HSC promotedinto apoptosis by cycloheximide. TIMP-1 treated rat HSCdemonstrated reduced fragmentation of N-Cadherin.MethodsIsolation of rat HSCRat HSC were extracted by pronase and collagenase diges-tion and purified by centrifugal elutriation as previouslydescribed [7]. Extracted rat HSC were cultured on plasticfor 7–10 days in the presence of serum until activated.Stimulation of HSC apoptosis and examination of nuclear morphology by acridine orangeApoptosis of activated rat HSC was induced by exposureto gliotoxin (1.5 micromolar) or cycloheximide (50micromolar) in the presence of TIMP-1 (5 nanomolar) ora mutated TIMP-1 (T2G N-TIMP-1 with no MMP inhibi-tory activity: kind gift of Professor Hideaki Nagase). Fol-lowing a 4 hour incubation at 37°C, nuclear morphologywas assessed by adding acridine orange to each well (finalconcentration 1 µg/ml) and examining the cells underblue fluorescence. The total number of apoptotic cellswere counted and expressed as a percentage of the totalnumber of cells.Quantification of HSC apoptosis by Caspase-3 activity assayTo validate the acridine orange assay, HSC apoptosis wasfurther assessed by a colorimetric assay for Caspase-3activity (Calbiochem) following the manufacturer'sinstructions.Western blotting for N-Cadherin-RatHSC protein extracts from different conditions were stud-ied by Western blotting for N-Cadherin using a mousemonoclonal antibody to an intracellular epitope of N-Cadherin (Clone 3B9, Zymed, California). Normalisedprotein extracts (10 micrograms) were separated on 12%SDS PAGE gels. The samples were electrotransferred ontopolyvinylidene difluoride membrane. This was blockedusing 1% non fat dry milk in TBS for 1 hour. The mem-branes were incubated overnight with the primary anti-body (1:100 dilution) or a non immune control IgG as anegative control. The membranes were washed threetimes in 0.1% Tween TBS (TTBS) before addition of thesecondary antibody (rabbit anti mouse horseradish per-oxidase at 1:2000 dilution) in 0.5% non fat dry milk TBSfor 1 hour. After a further two washes with TTBS thenwater, the membranes were developed using ECL (Amer-sham Biosciences) and autoradiography according to themanufacturer's instructions.ResultsWild type TIMP-1 but not the inactive T2G mutant TIMP-1 reduces apoptosis induced by cycloheximideBoth acridine orange staining and Caspase-3 activity assaydemonstrated that the wild type TIMP-1 but not the T2Gmutant TIMP-1 significantly inhibited HSC apoptosisinduced by exposure to cycloheximide for 4 hours. Thissuggested that the inhibitory effect of TIMP-1 on rat HSCapoptosis was via effects on MMP inhibition rather thanan alternative mechanism.Cyclohexmide and gliotoxin both promote apoptosis of rat HSCExposure of rat HSC to cycloheximide or gliotoxin pro-moted apoptosis of these cells when assessed by acridineorange staining and was further confirmed by increasedcaspase-3 activity over untreated cells.Rat activated HSC express intact 135 kDa N-CadherinWestern blotting of rat activated HSC protein extractsclearly demonstrated an intact 135 kDa form of N-Cad-herin. Furthermore, 60 and 38 kD truncated forms of N-Cadherin were observed in protein extracts from rat acti-vated HSC cultured in serum.Cleavage of N-Cadherin observed during HSC apoptosisCleavage of N-Cadherin was demonstrated with theappearance of a 60 kDa fragment after 3–4 hours exposureto cycloheximide or gliotoxin. This fragmentation wasreduced by co-incubation with 5 nM recombinant TIMP-1 but not by the non-functional T2G mutant TIMP-1.Bioinformatic analysis of rat N-Cadherin reveals multiple potential MMP cleavage sitesAnalysis of the known amino acid sequence of rat N-Cad-herin reveals 19 potential cleavage sites for MMPs. Thissuggests that MMPs have a role at least in part in pericel-lular proteolysis that occurs during apoptosis of cultureactivated rat HSC.DiscussionPrevious studies have shown that TIMP-1 is able to reduceapoptosis of cultured rat and human HSC. This effect isthought to be because of its primary function as an inhib-itor of matrix metalloproteinases [4]. This observation hasled to the further study of which MMP and which sub-strates might be important in mediating HSC survival orapoptosis. This work has examined the fate of the cell sur-face protein N-Cadherin that is known to be up regulatedduring HSC activation. The activated rat HSC expressPage 2 of 3(page number not for citation purposes)Comparative Hepatology 2004, 3 http://www.comparative-hepatology.com/content/3/S1/S8Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central yours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralintact 135 kDa N-Cadherin that is degraded into smallerfragments during apoptosis induced by gliotoxin orcycloheximide. N-Cadherin fragmentation was reducedby exposure to TIMP-1 but not a non functional mutantTIMP-1 (the T2G mutant TIMP-1). Protein database anal-ysis indicated that rat and human N-Cadherin contain anumber of potential MMP cleavage sites. MMP inhibitorshave previously been demonstrated to promote survivalof fibroblasts through up regulation of N-Cadherin func-tion [6]. MMP cleavage of N-Cadherin may be an impor-tant mechanism promoting HSC apoptosis in recoveryfrom liver fibrosis.References1. Friedman SL: The cellular basis of hepatic fibrosis: Mechanismsand treatment strategies. N Engl J Med 1993, 328:1828-1835.2. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, PawleyS, Hovell C, Arthur MJP: Mechanisms of spontaneous resolutionof rat liver fibrosis: hepatic stellate cell apoptosis andreduced hepatic expression of metalloproteinase inhibitors.J Clin Invest 1998, 102:538-549.3. Issa R, Williams E, Trim N, Kendall T, Arthur MJ, Reichen J, BenyonRC, Iredale JP: Apoptosis of hepatic stellate cells: involvementin resolution of biliary fibrosis and regulation by solublegrowth factors. Gut 2001, 48:548-557.4. Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ,Benyon C, Iredale JP: Inhibition of Apoptosis of ActivatedHepatic Stellate Cells by Tissue Inhibitor of Metalloprotein-ase-1 Is Mediated via Effects on Matrix MetalloproteinaseInhibition. Implications for Reversibility of Liver Fibrosis. JBiol Chem 2002, 277:11069-11076.5. Li G, Satyamoorthy K, Herlyn M: N-cadherin-mediated intercel-lular interactions promote survival and migration ofmelanoma cells. Cancer Res 2001, 61:3819-3825.6. Ho AT, Voura EB, Soloway PD, Watson KL, Khokha R: MMP inhib-itors augment fibroblast adhesion through stabilization offocal adhesion contacts and up-regulation of cadherin func-tion. J Biol Chem 2001, 276:40215-40224.7. Arthur MJP, Friedman SL, Roll FJ, Bissell DM: Lipocytes from nor-mal rat liver release a neutral metalloproteinase thatdegrades basement membrane (type IV) collagen. J Clin Invest1989, 84:1076-1085.Page 3 of 3(page number not for citation purposes)

DM: Lipocytes from normal rat liver release a neutral metalloproteinase that degrades basement membrane (type IV) collagen.

Iredale JP: Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors. Gut

Iredale JP: Inhibition of Apoptosis of Activated Hepatic Stellate Cells by Tissue Inhibitor of Metalloproteinase-1 Is Mediated via Effects on Matrix Metalloproteinase Inhibition. Implications for Reversibility of Liver Fibrosis.

MJP: Mechanisms of spontaneous resolution of rat liver fibrosis: hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.

MMP inhibitors augment fibroblast adhesion through stabilization of focal adhesion contacts and up-regulation of cadherin function.

N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res

The cellular basis of hepatic fibrosis: Mechanisms and treatment strategies.

N-Cadherin cleavage during activated hepatic stellate cell apoptosis is inhibited by tissue inhibitor of metalloproteinase-1. [In supplement: 11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells]

Frank Murphy

Julian Waung

Jane Collins

Michael JP Arthur

Hideaki Nagase

Derek Mann

R Christopher Benyon

John P Iredale

Springer - Publisher Connector

BioMed CentralComparative Hepatology
ssOpen AcceProceedings
N-Cadherin cleavage during activated hepatic stellate cell apoptosis 
is inhibited by tissue inhibitor of metalloproteinase-1
Frank Murphy*1, Julian Waung1, Jane Collins2, Michael JP Arthur1, 
Hideaki Nagase3, Derek Mann1, R Christopher Benyon1 and John P Iredale1
Address: 1Liver group, Division of Infection, Inflammation and Repair, Southampton University, Southampton General Hospital, Tremona Road, 
Southampton SO16 6YD, UK, 2Mucosal Immunology, Southampton University, Tremona Road, Southampton, UK and 3The Kennedy Institute, 
Imperial College, 1 Aspenlea Road, London W6, UK
Email: Frank Murphy* - frm105@hotmail.com; Julian Waung - jw1197@soton.ac.uk; Jane Collins - jec3@soton.ac.uk; 
Michael JP Arthur - mja1@soton.ac.uk; Hideaki Nagase - h.nagase@ic.ac.uk; Derek Mann - dam@soton.ac.uk; R 
Christopher Benyon - rcb@soton.ac.uk; John P Iredale - J.P.Iredale@soton.ac.uk
* Corresponding author    
Abstract
Apoptosis of hepatic stellate cells (HSC) has previously been shown to occur during spontaneous
resolution of experimental liver fibrosis. TIMP-1 has also been shown to have a key role because
of its ability to inhibit apoptosis of HSC via matrix metalloproteinase (MMP) inhibition. This has led
to further study of novel substrates for MMPs that might impact on HSC survival. N-Cadherin is
known to mediate cell-cell contacts in fibroblasts. In this study we demonstrate that N-Cadherin
is expressed by activated rat HSC. Furthermore, during apoptosis of HSC, the N-Cadherin is
cleaved into smaller fragments. Apoptosis of HSC may be inhibited by TIMP-1. This is associated
with reduced fragmentation of N-Cadherin. N-Cadherin may have an important role in supporting
HSC survival while N-Cadherin cleavage may play a part in promoting HSC apoptosis in recovery
from liver fibrosis.
Introduction
The activated hepatic stellate cell plays a key role in liver
fibrosis [1]. During spontaneous recovery from experi-
mental liver fibrosis loss of activated hepatic stellate cells
(HSCs) has been demonstrated to be through apoptosis
or programmed cell death [2,3]. This has highlighted con-
trol of HSC apoptosis for further investigation. During
spontaneous resolution of experimental liver fibrosis
there is a change in the balance between matrix metallo-
proteinase (MMP) activity and their endogenous inhibi-
tor TIMP-1. This change favours matrix degradation.
During resolution of fibrosis there is a great reduction in
TIMP-1 expression. Correlating with this event there is a
fall in the numbers of activated HSCs. This observation
was recently studied in depth in vitro. TIMP-1 reduced
apoptosis of culture activated HSC in a dose dependent
manner. Inhibition of HSC apoptosis by TIMP-1 has pre-
viously been shown to be due to its action of MMP inhi-
bition [4]. This has led to the further study of potential
MMPs and MMP substrates on the cell surface that might
impact on HSC survival.
N-Cadherin, which mediates cell to cell contact, is
expressed in activated HSC. It has been shown to signal
via the beta-catenin pathway. Disruption of this interac-
tion with blocking antibodies has been shown to promote
apoptosis in melanoma cells [5]. Furthermore, MMP
inhibitors including TIMPs have been demonstrated to
from 11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells
Tucson, Arizona, USA, 25–29 August, 2002
Published: 14 January 2004
Comparative Hepatology 2004, 3(Suppl 1):S8
<supplement> <title> <p>11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells</p> </title> </supplement>
This article is available from: http://www.comparative-hepatology.com/content/3/S1/S8Page 1 of 3
(page number not for citation purposes)
Comparative Hepatology 2004, 3 http://www.comparative-hepatology.com/content/3/S1/S8promote fibroblast adhesion through stabilisation of
focal adhesion contacts and up regulation of Cadherin
function in vitro [6]. We studied the fate of N-Cadherin in
HSC during apoptosis induced by cycloheximide or glio-
toxin. We have demonstrated that activated rat HSC
express intact 135 kDa N-Cadherin and that during apop-
tosis of these cells the N-Cadherin is degraded into
smaller fragments. We have also demonstrated that TIMP-
1 is able to reduce apoptosis of activated HSC promoted
into apoptosis by cycloheximide. TIMP-1 treated rat HSC
demonstrated reduced fragmentation of N-Cadherin.
Methods
Isolation of rat HSC
Rat HSC were extracted by pronase and collagenase diges-
tion and purified by centrifugal elutriation as previously
described [7]. Extracted rat HSC were cultured on plastic
for 7–10 days in the presence of serum until activated.
Stimulation of HSC apoptosis and examination of nuclear 
morphology by acridine orange
Apoptosis of activated rat HSC was induced by exposure
to gliotoxin (1.5 micromolar) or cycloheximide (50
micromolar) in the presence of TIMP-1 (5 nanomolar) or
a mutated TIMP-1 (T2G N-TIMP-1 with no MMP inhibi-
tory activity: kind gift of Professor Hideaki Nagase). Fol-
lowing a 4 hour incubation at 37°C, nuclear morphology
was assessed by adding acridine orange to each well (final
concentration 1 µg/ml) and examining the cells under
blue fluorescence. The total number of apoptotic cells
were counted and expressed as a percentage of the total
number of cells.
Quantification of HSC apoptosis by Caspase-3 activity 
assay
To validate the acridine orange assay, HSC apoptosis was
further assessed by a colorimetric assay for Caspase-3
activity (Calbiochem) following the manufacturer's
instructions.
Western blotting for N-Cadherin-Rat
HSC protein extracts from different conditions were stud-
ied by Western blotting for N-Cadherin using a mouse
monoclonal antibody to an intracellular epitope of N-
Cadherin (Clone 3B9, Zymed, California). Normalised
protein extracts (10 micrograms) were separated on 12%
SDS PAGE gels. The samples were electrotransferred onto
polyvinylidene difluoride membrane. This was blocked
using 1% non fat dry milk in TBS for 1 hour. The mem-
branes were incubated overnight with the primary anti-
body (1:100 dilution) or a non immune control IgG as a
negative control. The membranes were washed three
times in 0.1% Tween TBS (TTBS) before addition of the
secondary antibody (rabbit anti mouse horseradish per-
oxidase at 1:2000 dilution) in 0.5% non fat dry milk TBS
for 1 hour. After a further two washes with TTBS then
water, the membranes were developed using ECL (Amer-
sham Biosciences) and autoradiography according to the
manufacturer's instructions.
Results
Wild type TIMP-1 but not the inactive T2G mutant TIMP-
1 reduces apoptosis induced by cycloheximide
Both acridine orange staining and Caspase-3 activity assay
demonstrated that the wild type TIMP-1 but not the T2G
mutant TIMP-1 significantly inhibited HSC apoptosis
induced by exposure to cycloheximide for 4 hours. This
suggested that the inhibitory effect of TIMP-1 on rat HSC
apoptosis was via effects on MMP inhibition rather than
an alternative mechanism.
Cyclohexmide and gliotoxin both promote apoptosis of rat 
HSC
Exposure of rat HSC to cycloheximide or gliotoxin pro-
moted apoptosis of these cells when assessed by acridine
orange staining and was further confirmed by increased
caspase-3 activity over untreated cells.
Rat activated HSC express intact 135 kDa N-Cadherin
Western blotting of rat activated HSC protein extracts
clearly demonstrated an intact 135 kDa form of N-Cad-
herin. Furthermore, 60 and 38 kD truncated forms of N-
Cadherin were observed in protein extracts from rat acti-
vated HSC cultured in serum.
Cleavage of N-Cadherin observed during HSC apoptosis
Cleavage of N-Cadherin was demonstrated with the
appearance of a 60 kDa fragment after 3–4 hours exposure
to cycloheximide or gliotoxin. This fragmentation was
reduced by co-incubation with 5 nM recombinant TIMP-
1 but not by the non-functional T2G mutant TIMP-1.
Bioinformatic analysis of rat N-Cadherin reveals multiple 
potential MMP cleavage sites
Analysis of the known amino acid sequence of rat N-Cad-
herin reveals 19 potential cleavage sites for MMPs. This
suggests that MMPs have a role at least in part in pericel-
lular proteolysis that occurs during apoptosis of culture
activated rat HSC.
Discussion
Previous studies have shown that TIMP-1 is able to reduce
apoptosis of cultured rat and human HSC. This effect is
thought to be because of its primary function as an inhib-
itor of matrix metalloproteinases [4]. This observation has
led to the further study of which MMP and which sub-
strates might be important in mediating HSC survival or
apoptosis. This work has examined the fate of the cell sur-
face protein N-Cadherin that is known to be up regulated
during HSC activation. The activated rat HSC expressPage 2 of 3
(page number not for citation purposes)
Comparative Hepatology 2004, 3 http://www.comparative-hepatology.com/content/3/S1/S8Publish with BioMed Central   and  every 
scientist can read your work free of charge
"BioMed Central will be the most significant development for 
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central 
yours — you keep the copyright
Submit your manuscript here:
http://www.biomedcentral.com/info/publishing_adv.asp
BioMedcentral
intact 135 kDa N-Cadherin that is degraded into smaller
fragments during apoptosis induced by gliotoxin or
cycloheximide. N-Cadherin fragmentation was reduced
by exposure to TIMP-1 but not a non functional mutant
TIMP-1 (the T2G mutant TIMP-1). Protein database anal-
ysis indicated that rat and human N-Cadherin contain a
number of potential MMP cleavage sites. MMP inhibitors
have previously been demonstrated to promote survival
of fibroblasts through up regulation of N-Cadherin func-
tion [6]. MMP cleavage of N-Cadherin may be an impor-
tant mechanism promoting HSC apoptosis in recovery
from liver fibrosis.
References
1. Friedman SL: The cellular basis of hepatic fibrosis: Mechanisms
and treatment strategies. N Engl J Med 1993, 328:1828-1835.
2. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley
S, Hovell C, Arthur MJP: Mechanisms of spontaneous resolution
of rat liver fibrosis: hepatic stellate cell apoptosis and
reduced hepatic expression of metalloproteinase inhibitors.
J Clin Invest 1998, 102:538-549.
3. Issa R, Williams E, Trim N, Kendall T, Arthur MJ, Reichen J, Benyon
RC, Iredale JP: Apoptosis of hepatic stellate cells: involvement
in resolution of biliary fibrosis and regulation by soluble
growth factors. Gut 2001, 48:548-557.
4. Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ,
Benyon C, Iredale JP: Inhibition of Apoptosis of Activated
Hepatic Stellate Cells by Tissue Inhibitor of Metalloprotein-
ase-1 Is Mediated via Effects on Matrix Metalloproteinase
Inhibition. Implications for Reversibility of Liver Fibrosis. J
Biol Chem 2002, 277:11069-11076.
5. Li G, Satyamoorthy K, Herlyn M: N-cadherin-mediated intercel-
lular interactions promote survival and migration of
melanoma cells. Cancer Res 2001, 61:3819-3825.
6. Ho AT, Voura EB, Soloway PD, Watson KL, Khokha R: MMP inhib-
itors augment fibroblast adhesion through stabilization of
focal adhesion contacts and up-regulation of cadherin func-
tion. J Biol Chem 2001, 276:40215-40224.
7. Arthur MJP, Friedman SL, Roll FJ, Bissell DM: Lipocytes from nor-
mal rat liver release a neutral metalloproteinase that
degrades basement membrane (type IV) collagen. J Clin Invest
1989, 84:1076-1085.Page 3 of 3
(page number not for citation purposes)


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N-Cadherin cleavage during activated hepatic stellate cell apoptosis is inhibited by tissue inhibitor of metalloproteinase-1. [In supplement: 11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells]

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