Epigenetic regulation of metalloproteinases and their inhibitors in rotator cuff tears

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.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Fed Sao Paulo, Dept Ortopedia & Traumatol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Disciplina Genet, Dept Morfol & Genet, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Patol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Ortopedia & Traumatol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Disciplina Genet, Dept Morfol & Genet, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Patol, Sao Paulo, SP, BrazilFAPESP: 2011/22548-2FAPESP: 2012/14768-5FAPESP: 2016/01392-8FAPESP: 2016/15785-1FAPESP: 2013/10691-0FAPESP: 2013/10791-5Web of Scienc