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
Research background

Matrix metalloproteinases (MMPs) maintain the homeostasis between fibrogenesis and fibrolytic processes in the liver. Few studies on the production and activity of liver MMPs and fibrosis progression have been performed in humans.

Research motivation

The correct determination of liver fibrosis stages is imperative for making the diagnosis and implementing therapeutic decisions. At present, there is no evidence of the production and activity of MMP-2, MMP-7 or MMP-9 or their correlation with fibrosis progression in serum samples from patients with liver diseases.

Research objectives

In the present prospective, cross-sectional, multicenter study, we assessed the production, activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC).

Research methods

We selected CHC patients from the Hospital General de México, “Dr. Eduardo Liceaga,” the Universidad Autónoma de Nuevo Leon and the Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán.” Patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®(F0, F1, F2, F3 or F4). Serum concentrations of MMP-2, -7 and -9 were determined. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. Area under the receiver operating characteristic curve was calculated in fibrosis degrees. Proteolytic activity was validated by chromogenic and enzymatic assays and serum concentration, and the regulation of tissue inhibitor of metalloproteinases-1 was tested in fibrosis progression.

Research results

We compared 119 CHC patients with 119 healthy subjects. MMP-2, -7 and -9 concentrations were higher in the patients with CHC than in the control subjects. No differences between the serum concentrations of MMP-2 and MMP-9 were found, but MMP-7 showed differential regulation in accordance with fibrosis stages as well as an acceptable receiver operating characteristic (0.705), in advanced fibrosis (F4). Collagenolytic MMP activity was maintained in F0 and F1 but decreased significantly in F2, F3 and F4. Gelatin activity was not observed in any stage of fibrosis. The concentration of tissue inhibitor of metalloproteinases-1 was lower in F2 and F4 compared with F0, F1 and healthy subjects. Inactive MMPs were found in the serum of the CHC patients.

Research conclusions

Elevated concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be used in the diagnosis of liver fibrosis and the treatment for its reversal in CHC.

Research perspectives

Given that MMP-2, -7 and -9 have not been simultaneously evaluated in the serum from liver fibrosis patients, MMPs could be used to improve the currently available diagnostic methods and as therapeutic targets. They could also be used as a monitoring tool in treatment-experienced patients that continue to present with liver fibrosis and develop cirrhosis and/or hepatocellular carcinoma.