Cholestasis occurs in a variety of clinical settings and often results in liver injury and secondary biliary
fibrosis. Several
matrix metalloproteinases (
MMPs) are upregulated in the liver during
cholestasis. The function of the major
interstitial collagenase, MMP-13, in the initial phase of
liver fibrosis is unknown. The aim of this study was to evaluate the role of MMP-13 during the development of
cholestasis-induced
liver fibrosis by comparing wild-type and MMP-13-deficient mice.
Cholestasis was induced by bile duct
ligation (BDL) for 5 days or 3 weeks. Activation and proliferation of hepatic stellate cells (HSCs) were detected by immunohistochemistry. Expression of MMP-13
mRNA increased significantly in BDL livers of WT mice. After BDL for 3 weeks
liver fibrosis was suppressed in MMP-13-deficient mice versus WT animals. Activation and proliferation of HSCs were also suppressed in livers of MMP-13-deficient mice after BDL. To clarify the mechanism of this suppression, samples from 5-day BDL mice were used for evaluation of liver injury. Compared with those in WT animals, serum ALT and the number of hepatic neutrophils were reduced in MMP-13-deficient mice. Increased expression of the
mRNA of inflammatory mediators such as
tumor necrosis factor-alpha (
TNF-alpha) was significantly suppressed in livers of MMP-13-deficient mice. Upregulation of fibrogenic markers, for example,
transforming growth factor beta1 (TGF-beta1), was also significantly suppressed in livers of MMP-13-deficient mice versus in WT mice. In conclusion, distinct from the known function of
interstitial collagenase to reduce
liver fibrosis by degrading the extracellular matrix, MMP-13 contributes to accelerating fibrogenesis in cholestatic livers by mediating the initial
inflammation of the liver.