The rock inhibitor fasudil does not protect against cartilage degeneration in a rat model of post-traumatic OA

Purpose: Osteoarthritis (OA) is a degenerative joint disease characterized largely by the deterioration and loss of articular cartilage in the synovial joint. There are currently no effective treatments that can slow or stop the progression of the disease, and the underlying pathobiology is poorly understood. Rho-kinase (ROCK) is activated downstream of transforming growth factor alpha, which promotes OA progression. Moreover, inhibition of ROCK reduces cartilage degeneration in an ex vivo osteochondral explant model (Appleton et al, 2010). However, the role of ROCK in post-traumatic OA in vivo has not been extensively examined. In this study we examine the effects of ROCK inhibition by the small molecule fasudil on cartilage in a surgically induced model of OA in rats. Methods: To induce post-traumatic OA, the anterior cruciate ligament was transected (ACLT) and a portion of the medial meniscus was removed in the right knee joint of Sprague-Dawley rats, while independent animals received sham surgery. Osmotic mini-pumps were installed at the time of surgery (immediate) or 2 weeks (delayed) after surgery to deliver fasudil or vehicle continuously. Animals were collected at 4 and 8 weeks following surgery, and the knee joints were examined for signs of cartilage degeneration via histological staining. Cartilage degeneration was assessed using the OARSI approved scoring system for rat studies (Gerwin et al, 2010). Behavioural measures assessing hind-limb weight bearing and spontaneous activities were taken over the course of the experiment. Results: OARSI scores demonstrated a similar level of cartilage degeneration in the operated knee joint of both fasudil and vehicle treated ACLT animals, in both the immediate and delayed treatment groups. Similarly, behavioural measures including ‘animal rearing’ and weight bearing on the operated joint were similar in these groups. Sham operated fasudil and vehicle treated animals showed similar cartilage degeneration scores, but were significantly lower than ACLT operated animals. Total animal and liver weights were not significantly different between groups, indicating no fasudil toxicity at the dose chosen. Conclusions: Inhibition of ROCK using small molecule inhibitor fasudil did not prevent progression of cartilage degeneration in this rat model of post-traumatic OA. Additional work will be needed to evaluate the role of ROCK in spontaneous OA as a potential therapeutic target.