Changes in the expression of matrix extracellular genes and TGFB family members in rotator cuff tears.

Lack of synthesis of extracellular matrix compounds may contribute to degeneration of the tendons. Thus, we aimed to evaluate the expression of extracellular matrix and TGFB family members in ruptured and non-ruptured tendons of the rotator cuff, as well as the effect of clinical factors on gene expression in tendon samples, and the relationship between histological findings and altered gene expression. Injured and non-injured supraspinatus tendon samples and subscapular non-injured tendon samples were collected from 38 patients with rotator cuff tears. Non-injured supraspinatus tendons were obtained from eight controls. Specimens were used for histological evaluation, quantification of collagen fibers, and mRNA and protein expression analyses. Increased COL1A1, COL1A2, COL3A1, COL5A1, FN1, TNC, and TGFBR1 mRNA expression was observed in the tear samples (p < 0.05). Duration of symptoms was correlated with the levels of collagen type I/III fibers (p = 0.032; ρ = 0.0447) and FN1 immunostaining (p = 0.031; ρ = 0.417). Smoking was associated with increased frequency of microcysts, myxoid degeneration, and COL5A1, FN1, TNC, and TGFB1 mRNA expression (p < 0.05). FN1 immunostaining was correlated with the number of years of smoking (p = 0.048; ρ = 0.384). Lower levels of collagen type I/III fibers were detected in samples with fissures (0 = 0.046). High frequency of microcysts was associated with increased COL5A1, FN1, and TNC expression (p < 0.05, for all comparisons). Neovascularization was associated with reduced FN1 (p = 0.035) and TGFBR1 expression (p = 0.034). Our findings show differential expression of matrix extracellular genes and TGFB family members in the degeneration process involved in rotator cuff tears. These molecular alterations are influenced by clinical factors. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2542-2553, 2018.

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.