MicroRNAs and Related Tissue Remodeling Genes in Rotator Cuff Repair in a Rat Model




Contreras, Erik

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The majority of rotator cuff tears seen clinically are atraumatic and chronic in nature, which can contribute to joint inflammation and tendon degeneration. Although some inflammation is vital to the healing process, excessive inflammation and high levels of matrix-degrading enzymes have been associated with impaired healing of the rotator cuff. The underlying factors regulating the level of inflammation in the injured rotator cuff still remain unclear. The purpose of this study was to investigate the expression of miRNAs in the setting of acute and delayed repair of a torn rotator cuff in a rat model. We hypothesized that the expression of miRNAs related to the inflammatory process would be altered in the injured rotator cuff compared to the control. Fourteen rats were randomized to either acute or delayed rotator cuff repair. Seven animals underwent detachment of the supraspinatus and infraspinatus tendons followed by immediate repair, while the remaining seven underwent delayed repair 2 weeks later. Sham surgery on the contralateral shoulder was used as a control. mRNA expression for COL1A1, COL3A1, TGF-β1, MMP-9, MMP-13 and IL-6 was determined and select samples were analyzed for miRNA profiles. Upon analysis, 57 miRNAs showed significant differences between groups, including 14 miRNAs with significant differences between acute and delayed repair groups (p<0.05). miRNA correlation analysis with mRNAs expression revealed two distinct groupings. The first grouping includes IL-6, MMP-13, and MMP-9, genes that are traditionally associated with inflammation and matrix degradation. The second grouping contains TGFβ1 and COL1A1, genes that are traditionally associated with the repair process. These findings suggest that groups of miRNA expression may play a more global role in regulating the balance between the inflammatory and repair processes, although any specific interactions have yet to be determined. Interestingly, IL-6 has been shown to promote increased levels of miR-18a* expression in hepatocytes, where it then acts in a positive feedback loop of the IL-6 signaling pathway. Our data, which shows a positive correlation between IL-6 and miR-18a* (R2=0.63), is consistent with these findings. We speculate that there may be a similar interaction between IL-6, miR-18a*, and the expression of downstream targets involved in rotator cuff inflammation and repair. These findings support our hypothesis that the expression of miRNAs related to the inflammatory process is significantly altered in the injured rotator cuff compared to the control tendon. Of particular interest is miR-18a*, which has been shown to increase levels of matrix-degrading enzymes, pro-inflammatory cytokines, and chemokines in arthritis synovial fibroblasts. This will require further experimentation in order to determine the precise gene targets and whether or not down-regulation of miR-18a* could lead to a mechanism by which one could decrease

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The 53rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Monday, January 26, 2015, 2-5 p.m., D1.602).
Each year the Medical Student Research Program awards students for the best oral presentation and the best poster presentation as judged by faculty across campus. This author received an award as one of the best oral presentations at this forum.

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Contreras, E., Wei, F., Shirley, Z., Shelton, W., Khazzam, M., & Chen, C. T. (2015, January 26). MicroRNAs and related tissue remodeling genes in rotator cuff repair in a rat model. Poster presented at the 53rd Annual Medical Student Research Forum, Dallas, TX. Retrieved from https://hdl.handle.net/2152.5/1511

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