Hepatoprotective effect of MMP-19 deficiency in a mouse model of chronic liver fibrosis.
Liver fibrosis is characterized by the deposition and increased turnover of extracellular matrix. This process is controlled by matrix metalloproteinases (MMPs), whose expression and activity dynamically change during injury progression. MMP-19, one of the most widely expressed MMPs, is highly expressed in liver; however, its contribution to liver pathology is unknown. The aim of this study was to elucidate the role of MMP-19 during the development and resolution of fibrosis by comparing the response of MMP-19-deficient (MMP19KO) and wild-type mice upon chronic liver CCl(4)-intoxication. We show that loss of MMP-19 was beneficial during liver injury, as plasma ALT and AST levels, deposition of fibrillar collagen, and phosphorylation of SMAD3, a TGF-ß1 signaling molecule, were all significantly lower in MMP19KO mice. The ameliorated course of the disease in MMP19KO mice likely results from a slower rate of basement membrane destruction and ECM remodeling as the knockout mice maintained significantly higher levels of type IV collagen and lower expression and activation of MMP-2 after 4 weeks of CCl(4)-intoxication. Hastened liver regeneration in MMP19KO mice was associated with slightly higher IGF-1 mRNA expression, slightly increased phosphorylation of Akt kinase, decreased TGF-ß1 mRNA levels and significantly reduced SMAD3 phosphorylation. In addition, primary hepatocytes isolated from MMP19KO mice showed impaired responsiveness towards TGF-ß1 stimulation, resulting in lower expression of Snail1 and vimentin mRNA. Thus, MMP-19-deficiency improves the development of hepatic fibrosis through the diminished replacement of physiological extracellular matrix with fibrotic deposits in the beginning of the injury, leading to subsequent changes in TGF-ß and IGF-1 signaling pathways.
Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.
Marketa
M
Jirouskova
Olga
O
Zbodakova
Martin
M
Gregor
Karel
K
Chalupsky
Lenka
L
Sarnova
Marian
M
Hajduch
Jiri
J
Ehrmann
Marie
M
Jirkovska
Radislav
R
Sedlacek
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000201:enzymology; D049109:Cell Proliferation; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D022781:Hepatocytes / Q000166:cytology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology*; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19