ABSTRACT
Following liver injury, hepatic stellate cells (HSCs) become activated and express
a combination of matrix metalloproteinases (MMPs) and their specific tissue inhibitors
(TIMPs). In the early phases of liver injury (and primary cell culture), HSCs transiently
express MMP-3, MMP-13, and uroplasminogen activator (uPA) and exhibit a matrix-degrading
phenotype. In the later stages of liver injury and HSC activation, the pattern changes
and the cells express a combination of MMPs that have the ability to degrade normal
liver matrix, while inhibiting degradation of the fibrillar collagens that accumulate
in liver fibrosis. This pattern is characterized by the combination of pro-MMP-2 and
membrane type 1 (MT1)-MMP expression, which drive pericellular generation of active
MMP-2 and local degradation of normal liver matrix. In addition there is a marked
increase in expression of TIMP-1 leading to a more global inhibition of degradation
of fibrillar liver collagens by interstitial collagenases (MMP-1/MMP-13). These pathways
play a significant role in the progression of liver fibrosis. Following cessation
of liver injury, the pattern reverses and TIMP-1 in particular is rapidly downregulated.
This phase is characterized by increasing activity of collagenases, degradation of
liver matrix, and regression of liver fibrosis.
KEYWORD
Cirrhosis - liver fibrosis - matrix degradation - matrix metalloproteinases - tissue
inhibitor of metalloproteinases
