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

Abstract

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.

Knee immobilization reproduces key arthrofibrotic phenotypes in mice

“…Conditions to immobilize the knee joint in animals are numerous, including external immobilization with tape, 20,21,32 joint compression, 33 suture fixation, 7 and metallic wire. 4,8,23,34,35 In choosing our method of immobilization, we were careful to balance the goals of the procedures (contracture formation) versus unintended consequences (OA).…”

“…Timepoints were chosen based upon current literature. 13,[20][21][22][23][24] Surgical procedures. All surgical procedures were conducted by a surgeon (LD), who was blinded to the endpoint of the animals, under general anaesthesia via inhalation of isoflurane (1% to 2% in oxygen) administered via a nosecone.…”

Metformin Alleviates Arthrofibrosis via Fibroblast Metabolic Reprogramming

“…Several reports have shown that metformin can prevent and even reverse fibrotic processes in multiple organs, including the kidney, lung, and liver (Feng et al, 2017; Han et al, 2021; Kheirollahi et al, 2019; Li et al, 2021; McCloskey et al, 2020; Mummidi et al, 2016; Rangarajan et al, 2018; Sato et al, 2016; Tang et al, 2021). A recent study confirmed the positive effect of metformin in suppressing joint capsular fibrosis in a mouse model of knee contracture (Tokuda et al, 2021). Previously, the antifibrotic action of metformin was reported to be primarily mediated via AMPK activation and the downstream signaling cascades in fibroblasts, leading to upregulated mitochondrial biogenesis and decreased lactate production (Rangarajan et al, 2018; Tang et al, 2021).…”

“…Several reports have shown that metformin can prevent and even reverse fibrotic processes in multiple organs, including the kidney, lung, and liver (Feng et al, 2017;Han et al, 2021;Kheirollahi et al, 2019;Li et al, 2021;McCloskey et al, 2020;Mummidi et al, 2016;Rangarajan et al, 2018;Sato et al, 2016;Tang et al, 2021). A recent study confirmed the positive effect of metformin in suppressing joint capsular fibrosis in a mouse model of knee contracture (Tokuda et al, 2021).…”

“…Several reports have shown that metformin can prevent and even reverse fibrotic processes in multiple organs, including the kidney, lung, and liver [16][17][18][19][20][21][22][23]. A recent study demonstrated the positive effect of metformin in suppressing joint capsular fibrosis in a mouse model of knee contracture [50]. Previously, the anti-fibrotic action of metformin was reported to be primarily 1 8 mediated via AMP-activated protein kinase (AMPK) activation and the downstream signaling cascades in fibroblasts, leading to upregulated mitochondrial biogenesis and decreased lactate production [15,17].…”