title: Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Sarah R
authors: SR
authors: Calabro
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Annette E
authors: AE
authors: Maczurek
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Alison J
authors: AJ
authors: Morgan
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Thomas
authors: T
authors: Tu
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Victoria W
authors: VW
authors: Wen
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Christine
authors: C
authors: Yee
authors: Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Auvro
authors: A
authors: Mridha
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Maggie
authors: M
authors: Lee
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: William
authors: W
authors: d'Avigdor
authors: Victorian Infectious Disease Laboratory, Melbourne, VIC, Australia.
authors: Stephen A
authors: SA
authors: Locarnini
authors: Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia; Liver Injury and Cancer, Centenary Institute, Sydney, NSW, Australia.
authors: Geoffrey W
authors: GW
authors: McCaughan
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors: Fiona J
authors: FJ
authors: Warner
authors: Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia.
authors: Susan V
authors: SV
authors: McLennan
authors: Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia.
authors: Nicholas A
authors: NA
authors: Shackel
mesh_terms: D000818:Animals; D051926:Basigin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000633:toxicity; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D006842:Hydrocarbons, Brominated; D034741:RNA, Small Interfering; D019714:Tissue Inhibitor of Metalloproteinases; D051926:Basigin; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C031387:carbon tetrabromide