Anti-inflammatory Drug Dexamethasone Treatment During the Remobilization Period Improves Range of Motion in a Rat Knee Model of Joint Contracture

Abstract

Joint inflammation following remobilization is an important factor in the progression of arthrogenic contracture. We evaluated the effects of an anti-inflammatory treatment during the remobilization period of recovery after joint immobilization in rats. Three groups of rats had their right knee joints immobilized for 3 weeks using an external fixator at a flexion of 140° to generate flexion contracture. Next, the fixation device was removed, allowing immobilized knees to freely move again for 1 or 7 days. These rats were daily injected with either the steroidal anti-inflammatory drug dexamethasone or saline. Untreated knees were used as controls. At 1 day of remobilization, gene expression of pro-inflammatory cytokines, interleukin (IL)-1β, and IL-6 were both increased in the posterior joint capsule, while dexamethasone treatment inhibited increase of these markers. Passive extension range of motion (ROM) was measured before and after myotomy of the knee flexors. Restriction of ROM before myotomy mainly represents the myogenic, and ROM after myotomy shows the arthrogenic changes. Joint immobilization reduced ROM both before and after myotomy. Seven days of remobilization improved ROM before but not after myotomy. Arthrogenic contracture progression following remobilization was characterized by fibrotic reactions of hypercellularity, upregulation of collagen genes, and increased type I and III collagen proteins in the posterior joint capsule. Dexamethasone treatment during the remobilization period improved both myogenic and arthrogenic contractures. Furthermore, remobilization-induced fibrotic reactions in the joint capsule were mostly prevented using dexamethasone. Anti-inflammatory treatment during the recovery period may be a potential therapeutic treatment for joint contracture.

Intra-Articular Injection of Mitomycin C Prevents Progression of Immobilization-Induced Arthrogenic Contracture in the Remobilized Rat Knee

“…After three weeks, the fixation device was removed and rats in the RM and RM+M groups were allowed to recover for one week (remobilization). It is known that one week of remobilization following three weeks of immobilization induces fibrotic reactions in the joint capsule and arthrogenic contracture progression (Kaneguchi et al 2017, Kaneguchi et al 2018a, Kaneguchi et al 2018b, Kaneguchi et al 2019. Rats in the IM group were analyzed immediately after removal of the fixator and represented data from immobilization without remobilization.…”

“…In contrast, arthrogenic factors largely contribute to severe joint contracture induced by prolonged (over four weeks) immobilization, and recovery by remobilization is not expected in these cases (Trudel et al 2014). Arthrogenic contracture also further progresses during remobilization following short-term (within three weeks) immobilization (Kaneguchi and Ozawa 2017, Kaneguchi et al 2017, Kaneguchi et al 2018a, Kaneguchi et al 2018b, Kaneguchi et al 2019, Trudel et al 2014. To avoid irreversible joint contracture, arthrogenic contracture should therefore be targeted.…”

“…For example, administration of decorin, which suppresses bioactivity of cell adhesion, as well as fibrotic regulators, such as transforming growth factor-beta, can improve restricted joint motion in the rabbit intra-articular adhesion model (Fukui et al 2001). However, several studies showed development of arthrogenic contracture without fibrosis in the periarticular connective tissue in spinal cord injury and immobilization models (Hagiwara et al 2010, Kaneguchi et al 2017, Kaneguchi et al 2018a, Kaneguchi et al 2018b, Kaneguchi et al 2019, Moriyama et al 2007. While it therefore remains controversial whether joint fibrosis is a major factor in arthrogenic contracture, development of fibrosis is observed in the joint capsule of remobilized joints together with progression of arthrogenic contracture (Kaneguchi et al 2017, Kaneguchi et al 2018a, Kaneguchi et al 2018b, Kaneguchi et al 2019.…”

“…However, several studies showed development of arthrogenic contracture without fibrosis in the periarticular connective tissue in spinal cord injury and immobilization models (Hagiwara et al 2010, Kaneguchi et al 2017, Kaneguchi et al 2018a, Kaneguchi et al 2018b, Kaneguchi et al 2019, Moriyama et al 2007. While it therefore remains controversial whether joint fibrosis is a major factor in arthrogenic contracture, development of fibrosis is observed in the joint capsule of remobilized joints together with progression of arthrogenic contracture (Kaneguchi et al 2017, Kaneguchi et al 2018a, Kaneguchi et al 2018b, Kaneguchi et al 2019. We previously showed that anti-inflammatory treatment using the steroidal drug dexamethasone can prevent remobilization-induced arthrogenic contracture progression by suppressing joint capsule fibrosis and fibroblast proliferation (Kaneguchi et al 2018b).…”

“…While it therefore remains controversial whether joint fibrosis is a major factor in arthrogenic contracture, development of fibrosis is observed in the joint capsule of remobilized joints together with progression of arthrogenic contracture (Kaneguchi et al 2017, Kaneguchi et al 2018a, Kaneguchi et al 2018b, Kaneguchi et al 2019. We previously showed that anti-inflammatory treatment using the steroidal drug dexamethasone can prevent remobilization-induced arthrogenic contracture progression by suppressing joint capsule fibrosis and fibroblast proliferation (Kaneguchi et al 2018b). Other studies using intra-articular adhesion models also reported that administration of anti-inflammatory agents such as celecoxib and botulinum toxin type A attenuates joint contracture and intra-articular adhesion as well as fibroblast proliferation (Baranowski et al 2019, Gao et al 2017, Li et al 2013a.…”