Department of Orthopaedic Surgery, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, Fukuoka, 807-8555, Japan.
Department of Orthopaedic Surgery and Sports Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Kitakyushu, Japan.
Sci Rep. 2021 Sep 9;11(1):17978. doi: 10.1038/s41598-021-97445-7.
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.
关节挛缩会导致患者严重不适。二甲双胍是目前应用最广泛的 2 型糖尿病口服药物之一，最近发现其也具有抑制组织纤维化的作用。然而，其在抑制关节挛缩组织纤维化中的作用尚不清楚。在这项研究中，我们研究了二甲双胍治疗抑制关节囊纤维化的作用及其最佳给药时间。通过使用夹板和胶带固定膝关节来诱导小鼠关节囊纤维化。在固定后每隔一天通过腹腔内给药二甲双胍。评估了组织学和免疫组织化学变化以及纤维化相关基因的表达。基于组织学和免疫组织化学评估，二甲双胍治疗可显著抑制关节囊纤维化。来自接受二甲双胍治疗的小鼠的关节囊组织也显示出纤维化相关基因表达降低。早期而非晚期给予二甲双胍治疗对关节囊纤维化的抑制作用与整个治疗期间相同。早期给予二甲双胍治疗的小鼠中，纤维化相关基因的表达受到最明显的抑制。这些研究表明，二甲双胍治疗可抑制关节囊纤维化，最佳给药时间是关节固定后早期；给药延迟超过 2 周效果较差。
