caa a22 4500 445797614 CHVBK 20180317145130.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10620-010-1296-0 doi (NATIONALLICENCE)springer-10.1007/s10620-010-1296-0 Loss of Matrix Metalloproteinase-2 Amplifies Murine Toxin-Induced Liver Fibrosis by Upregulating CollagenI Expression [Elektronische Daten] [Brian Radbill, Ritu Gupta, Maria Ramirez, Analisa DiFeo, John Martignetti, Carlos Alvarez, Scott Friedman, Goutham Narla, Raluca Vrabie, Robert Bowles, Yedidya Saiman, Meena Bansal] Background and Aims: Matrix metalloproteinase-2 (MMP-2), a typeIV collagenase secreted by activated hepatic stellate cells (HSCs), is upregulated in chronic liver disease and is considered a profibrotic mediator due to its proliferative effect on cultured HSCs and ability to degrade normal liver matrix. Although associative studies and cell culture findings suggest that MMP-2 promotes hepatic fibrogenesis, no invivo model has definitively established a pathologic role for MMP-2 in the development and progression of liver fibrosis. We therefore examined the impact of MMP-2 deficiency on liver fibrosis development during chronic CCl4 liver injury and explored the effect of MMP-2 deficiency and overexpression on collagenI expression. Methods: Following chronic CCl4 administration, liver fibrosis was analyzed using Sirius Red staining with quantitative morphometry and real-time polymerase chain reaction (PCR) in MMP-2−/− mice and age-matched MMP-2+/+ controls. These studies were complemented by analyses of cultured human stellate cells. Results: MMP-2−/− mice demonstrated an almost twofold increase in fibrosis which was not secondary to significant differences in hepatocellular injury, HSC activation or typeI collagenase activity; however, typeI collagen messenger RNA (mRNA) expression was increased threefold in the MMP-2−/− group by real-time PCR. Furthermore, targeted reduction of MMP-2 in cultured HSCs using RNA interference significantly increased collagenI mRNA and protein, while overexpression of MMP-2 resulted in decreased collagenI mRNA. Conclusions: These findings suggest that increased MMP-2 during the progression of liver fibrosis may be an important mechanism for inhibiting typeI collagen synthesis by activated HSCs, thereby providing a protective rather than pathologic role. Springer Science+Business Media, LLC, 2010 Cirrhosis nationallicence Fibrogenesis nationallicence TypeI collagen nationallicence Hepatic stellate cell nationallicence Matrix metalloproteinase-2 nationallicence Radbill Brian Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, 10029, New York, NY, USA aut Gupta Ritu Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut Ramirez Maria Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut DiFeo Analisa Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut Martignetti John Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut Alvarez Carlos Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut Friedman Scott Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut Narla Goutham Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut Vrabie Raluca Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut Bowles Robert Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut Saiman Yedidya Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut Bansal Meena Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/2(2011-02-01), 406-416 0163-2116 56:2<406 2011 56 10620 https://doi.org/10.1007/s10620-010-1296-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10620-010-1296-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Radbill Brian Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, 10029, New York, NY, USA aut NATIONALLICENCE 700 1- Gupta Ritu Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut NATIONALLICENCE 700 1- Ramirez Maria Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut NATIONALLICENCE 700 1- DiFeo Analisa Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut NATIONALLICENCE 700 1- Martignetti John Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut NATIONALLICENCE 700 1- Alvarez Carlos Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut NATIONALLICENCE 700 1- Friedman Scott Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut NATIONALLICENCE 700 1- Narla Goutham Departments of Medicine and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA aut NATIONALLICENCE 700 1- Vrabie Raluca Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut NATIONALLICENCE 700 1- Bowles Robert Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut NATIONALLICENCE 700 1- Saiman Yedidya Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut NATIONALLICENCE 700 1- Bansal Meena Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 11-70, Box 1123, 10029, New York, NY, USA aut NATIONALLICENCE 773 0- Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/2(2011-02-01), 406-416 0163-2116 56:2<406 2011 56 10620 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer