Hepatocyte Produced Matrix Metalloproteinases Are Regulated by CD147 in Liver Fibrogenesis

Abstract

BackgroundThe classical paradigm of liver injury asserts that hepatic stellate cells (HSC) produce, remodel and turnover the abnormal extracellular matrix (ECM) of fibrosis via matrix metalloproteinases (MMPs). In extrahepatic tissues MMP production is regulated by a number of mechanisms including expression of the glycoprotein CD147. Previously, we have shown that CD147 is expressed on hepatocytes but not within the fibrotic septa in cirrhosis [1]. Therefore, we investigated if hepatocytes produce MMPs, regulated by CD147, which are capable of remodelling fibrotic ECM independent of the HSC.MethodsNon-diseased, fibrotic and cirrhotic livers were examined for MMP activity and markers of fibrosis in humans and mice. CD147 expression and MMP activity were co-localised by in-situ zymography. The role of CD147 was studied in-vitro with siRNA to CD147 in hepatocytes and in-vivo in mice with CCl4 induced liver injury using ãCD147 antibody intervention.ResultsIn liver fibrosis in both human and mouse tissue MMP expression and activity (MMP-2, -9, -13 and -14) increased with progressive injury and localised to hepatocytes. Additionally, as expected, MMPs were abundantly expressed by activated HSC. Further, with progressive fibrosis there was expression of CD147, which localised to hepatocytes but not to HSC. Functionally significant in-vitro regulation of hepatocyte MMP production by CD147 was demonstrated using siRNA to CD147 that decreased hepatocyte MMP-2 and -9 expression/activity. Further, in-vivo α-CD147 antibody intervention decreased liver MMP-2, -9, -13, -14, TGF-β and α-SMA expression in CCl4 treated mice compared to controls.ConclusionWe have shown that hepatocytes produce active MMPs and that the glycoprotein CD147 regulates hepatocyte MMP expression. Targeting CD147 regulates hepatocyte MMP production both in-vitro and in-vivo, with the net result being reduced fibrotic matrix turnover in-vivo. Therefore, CD147 regulation of hepatocyte MMP is a novel pathway that could be targeted by future anti-fibrogenic agents.

Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis?

“…In situ hybridization and immunohistochemistry on tissue sections and primary isolated hepatocytes showed heterogeneous expression of MMP‐2, MMP‐3, and MMP‐13 as well as TIMP‐1 and TIMP‐2 in lobules in CCl 4 ‐induced fibrosis and with fibrosis resolution . This finding was validated by our group as we have found significant expression of MMP‐2, MMP‐9, MMP‐13, and MMP‐14 in human and murine hepatocytes mediated by the glycoprotein CD147 with liver injury . In vitro hepatocytes were shown to be essential for MMP‐2 activation in untreated HSC cultures, and this has been attributed to hepatocyte‐derived MT2‐MMP .…”

“…Degradation of fibrous tissue is accompanied by intrahepatic upregulation of MMP‐1, MMP‐2, and MMP‐8 and downregulation of TIMP‐1 and TIMP‐2 . The cellular origins of the MMPs leading to the resolution of fibrosis are HSCs, inflammatory infiltrate (in particular macrophages), and hepatocytes . Further, apoptosis of activated HSCs is known to be an important factor in the resolution of fibrosis .…”

“…39 The cellular origins of the MMPs leading to the resolution of fibrosis are HSCs, inflammatory infiltrate (in particular macrophages), and hepatocytes. 40 Further, apoptosis of activated HSCs is known to be an important factor in the resolution of fibrosis. 12 Interestingly, there is evidence that HSC apoptosis is inhibited by TIMP-1, which also decreases in injury resolution through the inhibition of MMP activity.…”

Anti-fibrotic Effects of Synthetic Oligodeoxynucleotide for TGF-β1 and Smad in an Animal Model of Liver Cirrhosis

“…Furthermore, hepatocytes have been investigated as a source of TIMPs and other matrix modulators protein. Thus, they could play a role in processes of fibrogenesis and fibrosis regeneration 59 . Fibrosis progresses by HSCs, and hepatocyte damage deteriorates 20 .…”

Metalloproteinases in liver fibrosis: current insights

“…14 MMPs act as a part of a proteolytic network, in which proteases activate each other by processing inactive proforms. For instance, it has been shown that proMMP-2 is activated by MT-MMP-1 (MMP-14) in complex with TIMP-2, 15 and further MMP-2 and MT-MMP-1 are activated by proMMP-13.…”