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Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis
Sarah R Calabro1, Annette E Maczurek1, Alison J Morgan1
1Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
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.
Insights
Hepatocytes produce matrix metalloproteinases (MMPs) regulated by CD147, offering a new target for anti-fibrotic therapies. Targeting CD147 reduces liver fibrosis by controlling MMPs and matrix turnover.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- The classical view attributes liver fibrosis to hepatic stellate cells (HSCs) producing extracellular matrix (ECM) via matrix metalloproteinases (MMPs).
- CD147, a glycoprotein regulating MMPs in other tissues, is expressed on hepatocytes but not HSCs in cirrhosis.
- This study investigates if hepatocytes, via CD147, produce MMPs that remodel fibrotic ECM independently of HSCs.
Purpose of the Study:
- To determine if hepatocytes produce MMPs regulated by CD147.
- To investigate the role of CD147 in regulating hepatocyte MMP production in liver fibrosis.
- To explore CD147 as a potential therapeutic target for liver fibrosis.
Main Methods:
- Examined MMP activity and fibrosis markers in human and mouse livers (non-diseased, fibrotic, cirrhotic).
- Co-localized CD147 expression and MMP activity using in-situ zymography.
- Utilized in-vitro siRNA for CD147 in hepatocytes and in-vivo α-CD147 antibody intervention in mice with CCl4-induced liver injury.
Main Results:
- MMP expression and activity (MMP-2, -9, -13, -14) increased with liver injury and localized to hepatocytes.
- CD147 was expressed on hepatocytes, not HSCs, in progressive fibrosis.
- In-vitro siRNA reduced hepatocyte MMP-2 and -9; in-vivo α-CD147 antibody decreased MMPs, TGF-β, and α-SMA in mice.
Conclusions:
- Hepatocytes produce active MMPs, with CD147 regulating their expression.
- Targeting CD147 modulates hepatocyte MMP production both in-vitro and in-vivo.
- CD147-mediated regulation of hepatocyte MMPs presents a novel pathway for anti-fibrotic therapies.
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