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.