Hepatocyte production of modulators of extracellular liver matrix in normal and cirrhotic rat liver

León, María del Carmen Garcíade; Montfort, Irmgard; Montes, Eusebio Tello; Vancell, Rosario López; García, Alfonso Olivos; González-Canto, Augusto; Néquiz-Avendaño, Mario; Pérez-Tamayo, Ruy

doi:10.1016/j.yexmp.2005.03.008

Cited by 43 publications

(25 citation statements)

References 56 publications

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“…Our results strongly support previous studies that demonstrated expression of MMP-13 in scar-associated macrophages and hepatocytes in CCl 4 -injured liver. [26][27][28] Other studies have shown that activated HSCs express MMP-13 in vivo 19 and in culture. 29,30 Cytokines, such as IL-1 and TGF-␤, stimulate MMP-13 production in cultured-HSCs, 30,31 which was also found in our study.…”

Section: Discussionmentioning

confidence: 99%

Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis

et al. 2006

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Section: Discussionmentioning

confidence: 99%

Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis

et al. 2006

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“…However, hepatocytes are known to participate actively in the ECM modulation. 43 MMP activity is regulated by the TIMPs, which bind in substrate-and tissue-specific manners to MMPs, blocking their proteolytic activity. 44 During fibrosis, TIMP mRNA and protein levels dramatically increase, while MMP levels increase modestly or remain relatively static.…”

Section: A-msh Gene Transfer Attenuates Hepatic Fibrosis C-h Wang Et Almentioning

confidence: 99%

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

et al. 2006

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Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. a-Melanocyte-stimulating hormone (a-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that a-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether a-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. a-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that a-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that a-MSH gene therapy attenuated the liver transforming growth factor-b1, collagen a1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of a-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, a-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, a-MSH gene therapy reversed established liver fibrosis in mice and prevented the upregulated fibrogenic and pro-inflammatory gene responses after TAA administration. Its collagenolytic effect might be attributed to MMP and TIMP modulation. Hence, a-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

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“…MMPs are abundantly produced by hepatic stellate cells (HSC) within the dense fibrotic bands, which surround nodules of hepatocytes. Further, MMPs are also secreted by other intrahepatic cell populations including inflammatory cells and hepatocytes [10]–[12]. However, the role of MMPs originating from non-HSC intrahepatic cell populations, such as hepatocytes [12], has not until recently been attributed a significant role in the ECM remodelling associated with progressive fibrosis.…”

Section: Introductionmentioning

confidence: 99%

“…Further, MMPs are also secreted by other intrahepatic cell populations including inflammatory cells and hepatocytes [10]–[12]. However, the role of MMPs originating from non-HSC intrahepatic cell populations, such as hepatocytes [12], has not until recently been attributed a significant role in the ECM remodelling associated with progressive fibrosis. MMP-10 has been shown to be expressed by hepatocytes, cholangiocytes and macrophages and can clearly alter fibrogenesis in a non-HSC dependent manner [13].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte Produced Matrix Metalloproteinases Are Regulated by CD147 in Liver Fibrogenesis

et al. 2014

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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.

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Hepatocyte production of modulators of extracellular liver matrix in normal and cirrhotic rat liver

Cited by 43 publications

References 56 publications

Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis

Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

Hepatocyte Produced Matrix Metalloproteinases Are Regulated by CD147 in Liver Fibrogenesis

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