Nintedanib reduces severity of post-traumatic joint contracture by modulating fibrosis and inflammation

Abstract This study investigates the potential of nintedanib, a tyrosine kinase inhibitor with antifibrotic and anti-inflammatory properties, to mitigate post-traumatic joint contracture (PTJC) in a rat model. Given the lack of effective pharmacological treatments for this debilitating condition, this study aims to address the unmet need for non-surgical interventions by targeting the underlying fibrotic and inflammatory processes. A total of 26 male Sprague–Dawley rats were subjected to standardized knee trauma and immobilization for 2 weeks. Rats were randomized into two groups: a nintedanib treatment group (5 mg/kg taken twice daily, n = 13) and a placebo group ( n = 13). Joint mobility was evaluated biomechanically by measuring the contracture angle (CA) and resistance to extension. Posterior joint capsule tissues were analyzed histologically and via qPCR for profibrotic gene expression, including α-Sma , Il-6 , Tgf-β1 , Nf-κb , and Ctgf . Nintedanib treatment significantly reduced CA compared to placebo (68.1° ± 12.6° vs. 84.8° ± 11.1°, p < 0.01), indicating improved joint mobility. Knee extension in the nintedanib-treated rats required less force, particularly at lower extension angles ( p < 0.05). Molecular analysis showed a marked reduction in α-Sma expression, a myofibroblast marker, in the nintedanib group compared to placebo (11-fold decrease, p < 0.05). Histological examinations revealed relatively fewer myofibroblasts in the posterior joint capsule of rats treated with nintedanib. Nintedanib effectively mitigates fibrosis and inflammation in a rat model of PTJC, enhancing joint mobility and reducing profibrotic gene expression. These findings support further exploration of nintedanib as a pharmacological therapy for PTJC in clinical settings. Key messages Nintedanib is a promising candidate for the prevention of post-traumatic joint contracture. Oral administration of nintedanib (5 mg twice daily) over a period of 2 weeks improves joint mobility in post-traumatic joint contracture (PTJC). Nintedanib reduces the relative number of myofibroblasts. A significant reduction in α-SMA expression levels under the influence of nintedanib indicates a slowed transition of fibroblasts to myofibroblasts.