Liver fibrosis progression and regression in matrix metalloproteinase-8 deficient mice
Matrix Metalloproteinases (MMPs) are a family of enzymes involved in various processes such as modulation of inflammation, matrix remodeling and collagen turnover. MMP-8 plays a yet ill-defined role in liver fibrogenesis and fibrolysis. Thus, we investigated the role of MMP-8 in toxin-induced liver fibrosis and fibrosis regression using MMP-8 knock-out mice.
Six week old female MMP-8 KO mice (n = 10 per group) on a C57/BL6J background were treated according to an optimized carbon tetrachloride (CCl4)- and thioacetamide (TAA) fibrosis-induction protocol for 4 weeks and 8 weeks. C57/BL6J wildtype mice were used as controls. For the fibrosis regression study, mice were harvested at 5 day, 2 weeks, and 4 weeks after 4 weeks of hepatotoxin treatment. Parameters of liver fibrosis (hydroxyproline, Sirius red morphometry) and transcript levels related to fibrogenesis and fibrolysis (qPCR) were determined at sacrifice.
After CCl4- and TAA-treatment for 4 weeks livers of MMP-8 KO mice did not demonstrate any microscopic difference in fibrosis or liver architecture. However, TAA-treated MMP-8 KO mice showed significantly decreased collagen accumulation compared to the wild type mice at 8 weeks. There were no significant differences in the expression of most fibrosis and fibrolysis related transcripts at 4 weeks. However, at 8 weeks both CCl4- and TAA-treated MMP-8 KO mice showed a significant up-regulation of MMP-9 and IL-10 mRNA and a significant down-regulation of TGFβ1 mRNA compared to wild type controls. After toxin withdrawal MMP-8 KO mice showed more rapid recoveries than wildtype controls in both fibrosis models. Here, livers of CCl4 fibrotic wild type mice showed an upregulation of transcripts for proinflammatory CCR7, CXCR3 and TGFβ1 compared to MMP-8 KO mice. TAA wildtype mice demonstrated a decrease in the level of MMP-13 and CCL3.
MMP-8 promotes toxin-induced fibrosis progression by a suppression of MMP-9 and IL-10 production. In fibrosis regression, the absence of MMP-8 may accelerate the recruitment and activation of inflammatory cells. Some of the unexpected findings are likely related to the function of MMP-8 not only as a collagenase but also as a profibrogenic modulator for proinflammatory cytokines, chemokines and their receptors.