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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Physiol+Lung+Cell+Mol+Physiol
2014 ; 306
(11
): L1006-15
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Matrix metalloproteinase-9 activates TGF-? and stimulates fibroblast contraction
of collagen gels
#MMPMID24705725
Kobayashi T
; Kim H
; Liu X
; Sugiura H
; Kohyama T
; Fang Q
; Wen FQ
; Abe S
; Wang X
; Atkinson JJ
; Shipley JM
; Senior RM
; Rennard SI
Am J Physiol Lung Cell Mol Physiol
2014[Jun]; 306
(11
): L1006-15
PMID24705725
show ga
Matrix metalloproteinase-9 (MMP-9) is a matrix-degrading enzyme implicated in
many biological processes, including inflammation. It is produced by many cells,
including fibroblasts. When cultured in three-dimensional (3D) collagen gels,
fibroblasts contract the surrounding matrix, a function that is thought to model
the contraction that characterizes both normal wound repair and fibrosis. The
current study was designed to evaluate the role of endogenously produced MMP-9 in
fibroblast contraction of 3D collagen gels. Fibroblasts from mice lacking
expression of MMP-9 and human lung fibroblasts (HFL-1) transfected with MMP-9
small-interfering RNA (siRNA) were used. Fibroblasts were cast into type I
collagen gels and floated in culture medium with or without transforming growth
factor (TGF)-?1 for 5 days. Gel size was determined daily using an image analysis
system. Gels made from MMP-9 siRNA-treated human fibroblasts contracted less than
control fibroblasts, as did fibroblasts incubated with a nonspecific MMP
inhibitor. Similarly, fibroblasts cultured from MMP-9-deficient mice contracted
gels less than did fibroblasts from control mice. Transfection of the
MMP-9-deficient murine fibroblasts with a vector expressing murine MMP-9 restored
contractile activity to MMP-9-deficient fibroblasts. Inhibition of MMP-9 reduced
active TGF-?1 and reduced several TGF-?1-driven responses, including activity of
a Smad3 reporter gene and production of fibronectin. Because TGF-?1 also drives
fibroblast gel contraction, this suggests the mechanism for MMP-9 regulation of
contraction is through the generation of active TGF-?1. This study provides
direct evidence that endogenously produced MMP-9 has a role in regulation of
tissue contraction of 3D collagen gels mediated by fibroblasts.
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