Clinical and Translational Research
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 27, 2021; 13(2): 218-232
Published online Feb 27, 2021. doi: 10.4254/wjh.v13.i2.218
Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients
Moises Martinez-Castillo, Abigail Hernandez-Barragan, Ivonne Flores-Vasconcelos, Marina Galicia-Moreno, Dorothy Rosique-Oramas, Jose Luis Perez-Hernandez, Fatima Higuera-De la Tijera, Eduardo E Montalvo-Jave, Aldo Torre-Delgadillo, Paula Cordero-Perez, Linda Muñoz-Espinosa, David Kershenobich, Gabriela Gutierrez-Reyes
Moises Martinez-Castillo, Abigail Hernandez-Barragan, Ivonne Flores-Vasconcelos, Dorothy Rosique-Oramas, Gabriela Gutierrez-Reyes, Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
Marina Galicia-Moreno, Department of Molecular Biology and Genomics, Institute of Molecular Biology in Medicine and Gene Therapy, Health Science University Center, University of Guadalajara, Guadalajara 06726, Mexico
Jose Luis Perez-Hernandez, Fatima Higuera-De la Tijera, Department of Gastroenterology, General Hospital of Mexico “Dr. Eduardo Liceaga,” Mexico City 06726, Mexico
Eduardo E Montalvo-Jave, Department of General Surgery, General Hospital of Mexico “Dr. Eduardo Liceaga,” School of Medicine, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
Aldo Torre-Delgadillo, David Kershenobich, Hepatology and Liver Transplant, National Institute of Medical Sciences and Nutrition “Salvador Zubirán,” Mexico City 06726, Mexico
Paula Cordero-Perez, Linda Muñoz-Espinosa, University Hospital “Dr. José Eleuterio González,” Autonomous University of Nuevo Leon, Monterrey 06726, Mexico
Author contributions: Gutierrez-Reyes G and Kershenobich D contributed to the study design; Perez-Hernandez JL, Higuera-De la Tijera F, Montalvo-Jave E, Torre-Delgadillo A, Cordero-Perez P and Muñoz-Espinosa L contributed to the clinical evaluation; Cordero-Perez P and Rosique-Oramas D contributed to the biochemical evaluation of patients; Flores-Vasconcelos I and Gutierrez-Reyes G contributed to the data collection; Martinez-Castillo M, Hernandez-Barragan A, Flores-Vasconcelos I and Galicia-Moreno M contributed to the matrix metalloproteinases assessment; Martinez-Castillo M and Gutierrez-Reyes G contributed to the manuscript writing; Gutierrez-Reyes G contributed to the critical revision of the manuscript; All authors read and approved the final manuscript.
Supported by the National Council for Science and Technology, No. SALUD-2016-272579 and No. PAPIIT-UNAM TA200515.
Institutional review board statement: The study was previously approved by the institutional ethics committees of the Hospital General de México (HG/DI/16/107/03/082) and the Universidad Nacional Autónoma de México (FMD/DI/15/2015), guaranteeing its performance in accordance with the ethical principles described in the 1975 Declaration of Helsinki.
Informed consent statement: All participants provided written statements of informed consent prior to study enrollment.
Conflict-of-interest statement: The authors have no conflict of interest or financial conflict with any organization or entity.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Gabriela Gutierrez-Reyes, PhD, Academic Researcher, Professor, Research Scientist, Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Dr. Balmis 148 Col Doctores Cuauhtemoc, Mexico City 06726, Mexico.
Received: October 2, 2020
Peer-review started: October 2, 2020
First decision: December 3, 2020
Revised: December 14, 2020
Accepted: December 28, 2020
Article in press: December 28, 2020
Published online: February 27, 2021

Matrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans.


To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC).


A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®. Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.


Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 (P < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; P < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 (P < 0.001).


High concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.

Keywords: Extracellular matrix, Matrix metalloproteinases, Liver fibrosis, Chronic hepatitis C, Fibrogenesis, Fibrolysis

Core Tip: The relevance of this prospective study was to evaluate the role of matrix metalloproteinases in the pathophysiology of liver fibrosis in chronic hepatitis C patients. Matrix metalloproteinases could be used as possible therapeutic targets and as a monitoring tool in treatment-experienced patients that continue to present with liver fibrosis and develop cirrhosis and/or hepatocellular carcinoma.