Evaluation of Novel Therapeutic Agents for Modulation of the Inflammatory Response in Rotator Cuff Tendinopathy Utilizing a Mouse Model of Subacromial Impingement

Abstract

Background: Rotator cuff disease is prevalent and can cause significant disability. Local subacromial corticosteroid injections (CSIs) have been a mainstay of nonoperative management despite concerns regarding their potential for adverse effects on tendon and muscle tissue. We identified 3 potential molecular targets that could be inhibited by alternative, currently available treatments. Purpose: To compare the effects of losartan (LOS), anakinra (AK), and alpha-2-macroglobulin (A2M), not previously utilized in the treatment of rotator cuff disease, with CSI-treated and nontreated controls in a murine model of rotator cuff tendinopathy. Study Design: Controlled laboratory study. Methods: A total of 90 twelve-week-old male C57BL/6J mice were placed into 6 different groups (n = 15 mice per group). Group 1 underwent a sham procedure with no treatment (sham controls). Group 2 underwent placement of a metal clip in bilateral shoulders to induce impingement on the rotator cuff but received no further treatment. All mice receiving treatments (groups 3-6) underwent bilateral clip impingement surgery on day 0. On day 21, subacromial injections of CSI, AK, or A2M were performed, and LOS was administered via drinking water. All mice were sacrificed at 6 weeks after the initial impingement surgery. The supraspinatus tendons and muscles were harvested. Histology, biomechanical testing, flow cytometry, gene expression, and gait analysis were performed. The significance level was set at P = .05 for all statistical analyses. Results: Flow cytometry demonstrated that treatment groups exhibited individual stromal cell marker profiles more similar to sham controls than to the impingement control groups, with significantly higher percentages of CD51+, CD73+, CD90.2+, CD105+, and CD146+ cells compared with the impingement control group. Gene expression analysis demonstrated significantly decreased pathway scores for cytokine signaling, inflammasome, phagocytic cell function, oxidative stress, and proteotoxic stress in the treatment groups compared with the impingement control group. Conclusion: These novel therapeutic agents may have utility in promoting a favorable environment for stromal progenitor cells and decreasing cytokine signaling, inflammatory responses, and stress pathways associated with subacromial impingement. Clinical Relevance: Further investigation into these agents and the underlying cellular and molecular mechanisms of inflammation may allow for the utilization of alternatives to CSIs.