Expression of matrix metalloproteinase-2 and -14 persists during early resolution of experimental liver fibrosis and might contribute to fibrolysis

• Published in: Liver international 2004-10, Vol.24 (5), p.492-501
• Main Authors: Zhou, Xiaoying, Hovell, Christopher J., Pawley, Susannah, Hutchings, Matthew I., Arthur, Michael J. P., Iredale, John P., Benyon, R. Christopher
• Format: Article
• Language: English
• Subjects: Adult; Animals; collagenase; Disease Models, Animal; Fibrosis - metabolism; Fibrosis - pathology; hepatic stellate cell; Humans; Liver Cirrhosis, Experimental - enzymology; Liver Cirrhosis, Experimental - pathology; liver fibrosis; Male; matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Middle Aged; Rats; Rats, Sprague-Dawley; Recovery of Function; RNA, Messenger - metabolism; tissue inhibitor of metalloproteinase; Tissue Inhibitor of Metalloproteinase-2 - metabolism
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/j.1478-3231.2004.0946.x

: Background/Aims: Resolution of liver fibrosis is possible but the identity of the matrix metalloproteinases (MMPs) which degrade the accumulated collagens is uncertain. We examined MMP‐2 and MMP‐14 expression in established and resolving fibrosis to assess their role in resolution of liver fibrosis. Methods: MMP and tissue inhibitor of metalloproteinase (TIMP)‐2 expression in liver extracts was examined by ribonuclease protection assay, Western blotting and gelatin zymography. MMP activity was examined by 14C gelatin degradation. Results: In human cirrhotic liver, MMP‐14 mRNA was increased to 230–330% of normal liver expression. Both 63 kDa proenzyme and 60 kDa activated form were present. Cirrhotic livers had 270–320% of normal liver expression of MMP‐2 protein with 20–25% being the 62 Da activated form. Protein and mRNA for MMP‐2 and MMP‐14 progressively increased during 8 weeks of CCl4 treatment in rats. Between 3 and 7 days of resolution from CCl4 liver fibrosis, MMP‐2 and MMP‐14 persisted at elevated levels. Gelatinolytic activity in liver homogenates peaked at 7 days of recovery, being 140% above that in livers at peak fibrosis. Conclusions: Increased expression and activation of MMP‐2 and ‐14 occurs even under conditions of elevated TIMPs during liver fibrogenesis. During liver fibrosis resolution, as TIMP expression decays, the persistence of MMP‐2 and MMP‐14 may permit collagen degradation.