Epigenetic regulation of metalloproteinases and their inhibitors in rotator cuff tears.

Mariana Ferreira Leal,Alberto De Castro Pochini,Moises Cohen,Felipe De Seixas Alves,Paulo Santoro Belangero,Carina Cohen,Adrielle Martins De Oliveira,Leonardo Caires Dos Santos,Benno Ejnisman,Wânia Hiromi Yanaguizawa,Maria Teresa De Seixas Alves,Eduardo Antônio Figueiredo,Carlos Vicente Andreoli,Marília Cardoso Smith

doi:10.1371/journal.pone.0184141

Mariana Ferreira Leal, Alberto De Castro Pochini + Show 12 more

Open Access

https://doi.org/10.1371/journal.pone.0184141

Copy DOI

Journal: PloS one	Publication Date: Sep 13, 2017
Citations: 19	License type: CC BY 4.0

Affiliation: Universidade Federal de São Paulo

Abstract

Rotator cuff tear is a common orthopedic condition. Metalloproteinases (MMP) and their inhibitors (TIMP) seem to play a role in the development of joint injuries and in the failure of tissue healing. However, the mechanisms of regulation of gene expression in tendons are still unknown. Epigenetic mechanisms, such as DNA methylation and microRNAs regulation, are involved in the dynamic control of gene expression. Here, the mRNA expression and DNA methylation status of MMPs (MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14) and TIMPs (TIMP1-3) and the expression of miR-29 family members in ruptured supraspinatus tendons were compared with non-injured tendons of individuals without this lesion. Additionally, the gene expression and methylation status at the edge of the ruptured tendon were compared with macroscopically non-injured rotator cuff tendon samples from the anterior and posterior regions of patients with tendon tears. Moreover, the possible associations between the molecular alterations and the clinical and histologic characteristics were investigated. Dysregulated expression and DNA methylation of MMP and TIMP genes were found across the rotator cuff tendon samples of patients with supraspinatus tears. These alterations were influenced at least in part by age at surgery, sex, smoking habit, tear size, and duration of symptoms. Alterations in the studied MMP and TIMP genes may contribute to the presence of microcysts, fissures, necrosis, and neovascularization in tendons and may thus be involved in the tendon healing process. In conclusion, MMPs and their inhibitors are regulated by epigenetic modifications and may play a role in rotator cuff tears.

Highlights

Rotator cuff degeneration is a very common orthopedic condition, and there are multiple factors that eventually lead to a full-thickness rotator cuff tear [1]
Dysregulated expression and DNA methylation of Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP) occur across the rotator cuff tendon samples of patients with supraspinatus tears
We originally described that these alterations can be “spread” to non-rupture human tendons highlighting the effect of a tendon tear in the shoulder joint complex, which should be considered during the patient management since it can increase the risk of other tendon lesions

Summary

Introduction

Rotator cuff degeneration is a very common orthopedic condition, and there are multiple factors that eventually lead to a full-thickness rotator cuff tear [1]. The incidence rate of degenerative rotator cuff tears increases with age; such tears can become an increasingly prevalent clinical problem [2]. Surgical repair of tendon tears significantly improves pain and function; retearing of the rotator cuff is not an infrequent occurrence [2]. MMPs and TIMPs regulation in tendon tears. Tecnologico (CNPq): fellowship to MC and MCS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study

Methods

Results

Conclusion