Dual Endothelin Receptor Inhibition with Bosentan Does Not Prevent the Early Formation of Post-Traumatic Joint...

Background: Post-traumatic joint contracture (PTJC) remains one of the most prevalent and challenging complications arising from musculoskeletal trauma or surgical intervention. Conventional treatment modalities are largely reactive and address symptoms after onset, yet provide limited efficacy once contracture has developed. In contrast, pharmacological strategies targeting the underlying inflammatory and fibrotic pathways offer a promising strategy for preventing the development of PTJC altogether. Methods: A total of 26 male Sprague Dawley rats underwent standardized knee trauma followed by immobilization for a duration of two weeks. Rats were randomized into two groups. The experimental group (n = 13) received bosentan at a dosage of 50 mg/kg twice daily throughout the immobilization period. The control group (n = 13) received a placebo instead. Joint mobility was quantitatively assessed by measuring the contracture angle (CA) and resistance to extension. In addition, posterior joint capsule tissues were harvested for histological analysis and subjected to quantitative PCR (qPCR) to quantify the expression of profibrotic genes, including α-Sma, Il-6, Tgf-β1, Nfκ-b, Ctgf. Results: Bosentan had no relevant effect on the biomechanics of the contracture compared to the placebo group. The contracture angle was comparable between the groups (86.8° ± 14.1°, 84.8° ± 11.1°). Similarly, the force required to achieve knee joint extension was comparable between the groups. Gene expression analysis also provided no evidence of reduced expression of pro-inflammatory or profibrotic genes. Histological assessments revealed no change in the absolute or relative number of myofibroblasts, or in the number of vessels, in the posterior joint capsules of the rats treated with bosentan. Compared to the control group, the number of myofibroblasts significantly increased in both the bosentan and control groups (p < 0.001, one-way ANOVA). Conclusions: Bosentan's purported antifibrotic properties do not appear to confer a preventative effect on the development of PTJC. These findings suggest that, despite its potential in modulating fibrosis, bosentan does not mitigate the progression of the fibrotic condition. Furthermore, the involvement of endothelin-1 (ET-1) in the pathophysiology of PTJC remains yet to be fully understood, warranting further investigation.