Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures
Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures
Background and Aims: in addition to its crucial role in
dampening tissue-damaging immune responses in the
gut, transforming growth factor b (TGFb) is a potent
profibrogenic agent inducing collagen synthesis and
regulating the balance between matrix-degrading matrix
metalloproteinases (MMPs) and their inhibitors (TIMPs).
TGFb signalling was investigated by analysis of Smad
proteins and MMPs/TIMPs in the mucosa overlying
strictures in patients with Crohn’s disease (CD).
Methods: specimens were collected from macroscopically
normal mucosa overlying strictured and nonstrictured
gut of patients with fibrostenosing CD. Isolated
myofibroblasts were cultured with anti-TGFb blocking
antibody or TGFb1. TGFb transcripts were analysed by
quantitative reverse transcription-PCR (RT-PCR). Smad
proteins and MMPs were determined by immunoblotting.
MMP-12 activity was measured by a real-time MMP-12
activity assay. An in vitro wound-healing scratch assay
was used to assess myofibroblast migration.
Results: TGFb transcripts, phosphorylated Smad2–
Smad3 (pSmad2–3) and TIMP-1 proteins were higher in
mucosa overlying strictures than in mucosa overlying nonstrictured
areas. In contrast, mucosa overlying strictured
gut had lower expression of Smad7, MMP-12 and MMP-
3. Myofibroblasts from mucosa overlying strictured gut
showed higher TGFb transcripts, a greater pSmad2–3
response to TGFb, increased TIMP-1, lower Smad7,
increased collagen production and reduced migration
ability compared with myofibroblasts from mucosa
overlying non-strictured gut. TGFb blockade increased
myofibroblast MMP-12 production and migration, more
obviously in myofibroblasts isolated from mucosa overlying
non-strictured compared with strictured gut.
Conclusions: changes in TGF-b signalling and MMP
production were identified in the mucosa overlying
strictures in CD which may give a window into the
process of fibrosis
777-789
Di Sabatino, A.
7e2802bd-ff3d-4578-862d-1d9c524b78a4
Jackson, C.L.
226ddeb9-4043-4ef5-80ba-9cf1e18a060b
Pickard, K.M.
9828c7f4-0beb-49b4-86b1-d4fddb7a854e
Buckley, M.
0a782ca9-25c4-4b3f-b08a-ca678bfbbc69
Rovedatti, L.
44d9bc48-27b6-43e8-9d23-59ce436ed759
Leakey, N.A.
6d46ef0c-ad1e-47bd-a948-51b947acacc6
Picariello, L.
5ea1083e-f0e1-4c21-b637-c96ca0819197
Cazzola, P.
dba67610-f042-4112-adab-025a164e813f
Monteleone, G.
bd762d44-920a-4c7d-afb3-b7a123399e73
MacDonald, T.T.
171334aa-638a-42b0-99f6-e860e2f0ca45
Pender, S.L.F.
62528b03-ec42-41bb-80fe-48454c2c5242
June 2009
Di Sabatino, A.
7e2802bd-ff3d-4578-862d-1d9c524b78a4
Jackson, C.L.
226ddeb9-4043-4ef5-80ba-9cf1e18a060b
Pickard, K.M.
9828c7f4-0beb-49b4-86b1-d4fddb7a854e
Buckley, M.
0a782ca9-25c4-4b3f-b08a-ca678bfbbc69
Rovedatti, L.
44d9bc48-27b6-43e8-9d23-59ce436ed759
Leakey, N.A.
6d46ef0c-ad1e-47bd-a948-51b947acacc6
Picariello, L.
5ea1083e-f0e1-4c21-b637-c96ca0819197
Cazzola, P.
dba67610-f042-4112-adab-025a164e813f
Monteleone, G.
bd762d44-920a-4c7d-afb3-b7a123399e73
MacDonald, T.T.
171334aa-638a-42b0-99f6-e860e2f0ca45
Pender, S.L.F.
62528b03-ec42-41bb-80fe-48454c2c5242
Di Sabatino, A., Jackson, C.L., Pickard, K.M., Buckley, M., Rovedatti, L., Leakey, N.A., Picariello, L., Cazzola, P., Monteleone, G., MacDonald, T.T. and Pender, S.L.F.
(2009)
Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn's disease strictures.
Gut, 58 (6), .
(doi:10.1136/gut.2008.149096).
Abstract
Background and Aims: in addition to its crucial role in
dampening tissue-damaging immune responses in the
gut, transforming growth factor b (TGFb) is a potent
profibrogenic agent inducing collagen synthesis and
regulating the balance between matrix-degrading matrix
metalloproteinases (MMPs) and their inhibitors (TIMPs).
TGFb signalling was investigated by analysis of Smad
proteins and MMPs/TIMPs in the mucosa overlying
strictures in patients with Crohn’s disease (CD).
Methods: specimens were collected from macroscopically
normal mucosa overlying strictured and nonstrictured
gut of patients with fibrostenosing CD. Isolated
myofibroblasts were cultured with anti-TGFb blocking
antibody or TGFb1. TGFb transcripts were analysed by
quantitative reverse transcription-PCR (RT-PCR). Smad
proteins and MMPs were determined by immunoblotting.
MMP-12 activity was measured by a real-time MMP-12
activity assay. An in vitro wound-healing scratch assay
was used to assess myofibroblast migration.
Results: TGFb transcripts, phosphorylated Smad2–
Smad3 (pSmad2–3) and TIMP-1 proteins were higher in
mucosa overlying strictures than in mucosa overlying nonstrictured
areas. In contrast, mucosa overlying strictured
gut had lower expression of Smad7, MMP-12 and MMP-
3. Myofibroblasts from mucosa overlying strictured gut
showed higher TGFb transcripts, a greater pSmad2–3
response to TGFb, increased TIMP-1, lower Smad7,
increased collagen production and reduced migration
ability compared with myofibroblasts from mucosa
overlying non-strictured gut. TGFb blockade increased
myofibroblast MMP-12 production and migration, more
obviously in myofibroblasts isolated from mucosa overlying
non-strictured compared with strictured gut.
Conclusions: changes in TGF-b signalling and MMP
production were identified in the mucosa overlying
strictures in CD which may give a window into the
process of fibrosis
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Published date: June 2009
Identifiers
Local EPrints ID: 72611
URI: http://eprints.soton.ac.uk/id/eprint/72611
ISSN: 0017-5749
PURE UUID: 53d511fe-130a-4e4b-8e25-b86a356acdd8
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Date deposited: 18 Feb 2010
Last modified: 14 Mar 2024 02:45
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Contributors
Author:
A. Di Sabatino
Author:
C.L. Jackson
Author:
K.M. Pickard
Author:
M. Buckley
Author:
L. Rovedatti
Author:
N.A. Leakey
Author:
L. Picariello
Author:
P. Cazzola
Author:
G. Monteleone
Author:
T.T. MacDonald
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