Effect of metformin treatment and its time of administration on joint capsular fibrosis induced by mouse knee immobilization

Joint contracture leads to major patient discomfort. Metformin, one of the most extensively used oral drugs against type 2 diabetes has recently been found to suppress tissue fibrosis as well. However, its role in suppressing tissue fibrosis in joint contractures remains unknown. In this study, we examined the role of metformin treatment in suppressing joint capsular fibrosis and the most effective time of its administration. Joint capsular fibrosis was induced by immobilizing the knee joints of mice using splints and tapes. Metformin was administered intraperitoneally every alternate day after immobilization. Histological and immunohistochemical changes and expression of fibrosis-related genes were evaluated. Metformin treatment significantly suppressed fibrosis in joint capsules based on histological and immunohistochemical evaluation. Joint capsular tissue from metformin-treated mice also showed decreased expression of fibrosis-related genes. Early, but not late, metformin administration showed the same effect on fibrosis suppression in joint capsule as the whole treatment period. The expression of fibrosis-related genes was most suppressed in mice administered with metformin early. These studies demonstrated that metformin treatment can suppress joint capsular fibrosis and the most effective time to administer it is early after joint immobilization; a delay of more than 2 weeks of administration is less effective.