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    Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.

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    Author
    Calabro, SR; Maczurek, AE; Morgan, AJ; Tu, T; Wen, VW; Yee, C; Mridha, A; Lee, M; d'Avigdor, W; Locarnini, SA; ...
    Date
    2014
    Source Title
    PLoS One
    Publisher
    Public Library of Science (PLoS)
    University of Melbourne Author/s
    Locarnini, Stephen
    Affiliation
    Microbiology and Immunology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Calabro, S. R., Maczurek, A. E., Morgan, A. J., Tu, T., Wen, V. W., Yee, C., Mridha, A., Lee, M., d'Avigdor, W., Locarnini, S. A., McCaughan, G. W., Warner, F. J., McLennan, S. V. & Shackel, N. A. (2014). Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.. PLoS One, 9 (7), pp.e90571-. https://doi.org/10.1371/journal.pone.0090571.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255702
    DOI
    10.1371/journal.pone.0090571
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116334
    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. CONCLUSION: 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.

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