Leal Mariana Ferreira, Caires Dos Santos Leonardo, Martins de Oliveira Adrielle, Santoro Belangero Paulo, Antônio Figueiredo Eduardo, Cohen Carina, de Seixas Alves Felipe, Hiromi Yanaguizawa Wânia, Vicente Andreoli Carlos, de Castro Pochini Alberto, Ejnisman Benno, Cardoso Smith Marília, de Seixas Alves Maria Teresa, Cohen Moises
Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
PLoS One. 2017 Sep 13;12(9):e0184141. doi: 10.1371/journal.pone.0184141. eCollection 2017.
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.
肩袖撕裂是一种常见的骨科病症。金属蛋白酶（MMP）及其抑制剂（TIMP）似乎在关节损伤的发生以及组织愈合失败过程中发挥作用。然而，肌腱中基因表达的调控机制仍不清楚。表观遗传机制，如DNA甲基化和微小RNA调控，参与基因表达的动态控制。在此，将冈上肌腱断裂患者的MMP（MMP1、MMP2、MMP3、MMP9、MMP13和MMP14）和TIMP（TIMP1 - 3）的mRNA表达及DNA甲基化状态，以及miR - 29家族成员的表达，与无此病变个体的未损伤肌腱进行比较。此外，将断裂肌腱边缘的基因表达和甲基化状态，与肌腱撕裂患者前后区域宏观上未损伤的肩袖肌腱样本进行比较。而且，研究了分子改变与临床和组织学特征之间的可能关联。在冈上肌撕裂患者的肩袖肌腱样本中发现了MMP和TIMP基因的表达失调及DNA甲基化。这些改变至少部分受手术年龄、性别、吸烟习惯、撕裂大小和症状持续时间的影响。所研究的MMP和TIMP基因的改变可能导致肌腱中出现微囊肿、裂隙、坏死和新生血管形成，因此可能参与肌腱愈合过程。总之，MMP及其抑制剂受表观遗传修饰调控，并可能在肩袖撕裂中起作用
