Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis

The 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...

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Published in:PloS one 2014-07, Vol.9 (7), p.e90571
Main Authors: Calabro, Sarah R, Maczurek, Annette E, Morgan, Alison J, Tu, Thomas, Wen, Victoria W, Yee, Christine, Mridha, Auvro, Lee, Maggie, d'Avigdor, William, Locarnini, Stephen A, McCaughan, Geoffrey W, Warner, Fiona J, McLennan, Susan V, Shackel, Nicholas A
Format: Article
Language:English
Subjects:
Active control
Animal tissues
Animals
Basigin - chemistry
Basigin - genetics
Basigin - metabolism
Bile
Biology
Biology and Life Sciences
Carbon tetrachloride
CD147 antigen
Cells, Cultured
Chemical and Drug Induced Liver Injury - etiology
Chemical and Drug Induced Liver Injury - metabolism
Cirrhosis
Ethics
Extracellular matrix
Fibrosis
Gastroenterology
Gelatinase A
Glycoproteins
Hepatocytes
Hepatocytes - cytology
Hepatocytes - metabolism
Hepatology
Humans
Hydrocarbons, Brominated - toxicity
Immunohistochemistry
Injuries
Intervention
Liver
Liver - metabolism
Liver - pathology
Liver cirrhosis
Liver Cirrhosis - metabolism
Liver Cirrhosis - pathology
Matrix Metalloproteinase 2 - genetics
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - genetics
Matrix Metalloproteinase 9 - metabolism
Matrix metalloproteinases
Matrix Metalloproteinases - genetics
Matrix Metalloproteinases - metabolism
Medical schools
Medicine and health sciences
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Polymerase Chain Reaction
RNA Interference
RNA, Small Interfering - metabolism
Rodents
Septum
siRNA
Stellate cells
Tissue Inhibitor of Metalloproteinases - metabolism
Transforming growth factors
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Summary:The 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. Non-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. In 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. We 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0090571