Osteoarthritis (OA) is the most common of arthritic conditions. It is estimated to affect around 10 million people in the UK alone and is associated with several symptoms, including joint pain and stiffness, that can significantly affect patients’ quality of life. The condition is characterised by a loss of joint cartilage, which occurs due to an imbalance in how chondrocytes maintain the cartilage. As the disease progresses, bone underneath the cartilage becomes exposed, leading to nerve irritation and pain in the affected joints.
There is currently no therapeutic treatment to prevent the development of osteoarthritis with available treatments focusing on the alleviation of OA symptoms. As a result, OA often continues to progress despite best practices in managing activity and pain. There is, therefore, a clear need to develop treatment strategies that are effective in controlling and preventing the progression of the disease.
Medical Cannabis and Osteoarthritis
Records of medical cannabis being used in the treatment of pain, and many other symptoms, date back thousands of years. In recent decades, scientific and clinical research into cannabis compounds has renewed with a particular focus on cannabinoids.
Cannabinoids directly interact with the endocannabinoid system (ECS), a system of receptors, transmitters, and enzymes which play regulatory roles in the nervous and immune systems, among others. Cannabinoid receptors (namely CB1 and CB2) are both expressed in cells that are involved in OA development, including subchondral osteoclasts, synovial fibroblasts, and chondrocytes.
Previous studies have revealed changes in cannabinoid receptor expression in OA-affected joints. Moreover, recent studies suggest that activation of cannabinoid receptors may be a promising target for future OA research. The authors of a recent series of studies aimed to assess the action of dimethylbutyl-deoxy-delta-8-THC (JWH-133), a selective CB2 agonist, on chondrocyte metabolism using both in vitro and in vivo studies.
Design of the Study
The researchers focused on the CB2 receptor, as it is expressed in peripheral neuronal tissue and cartilage, making it a candidate for both OA symptoms and disease activity. Activation of this receptor has been found to lead to reduced inflammation and generation of pain signals.
In the present study, the researchers used JWH-133 in a rat model of OA after chronic intra-articular injections. To induce OA-related changes in animal joints, the researchers administered a single injection of monoiodoacetate. After performing behavioural studies, the researchers collected cartilage tissue to analyse the level of matrix metalloproteinases and components of the ECS. Furthermore, to discover the mechanism of action of JWH-133, the researchers used cultures of human chondrocytes treated with monoiodoacetate and examined the effect of monoiodoacetate and JWH-133 on human chondrocyte viability and proliferation. Finally, through scratch-wound assays, they assessed the involvement of CB2 agonism in the proliferation and motility of chondrocytes.
Results of the Study
Results revealed significant increases in joint hypersensitivity after monoiodoacetate injection, as measured by pressure application measurement tests. An immediate development of pain behaviour lasted for 6 days, followed by an alleviation of symptoms from days 8 to 12, then further progressive, chronic pain development from day 14 until the experimental endpoint. In contrast, animals that were treated with saline experienced pain related to the procedure but did not develop chronic pain behaviour.
The treatment paradigm, consisting of three doses of JWH-133 (100 ng per knee joint), began at day 14 and continued until day 28. Alleviation of pain symptoms was observed at day 20 after monoiodoacetate administration. Treatment remained effective until the end of the behavioural experiment, showing a significant increase in withdrawal threshold in the JWH-133-treated group of animals.
Both CB1 and CB2 receptors were examined in cartilage samples collected at day 28 from animals treated with JWH-133. The researchers observed elevated levels of CB2 protein in OA-affected cartilage that was reduced by chronic administration of JWH-133. These findings demonstrated that the receptor for this compound was present in the intra-articular space, while the response of protein expression to the treatment suggested an effective dose of JWH-133.
Primary human chondrocytes were subjected to monoiodoacetate, JWH-133, and AM-630 (potent CB2 agonist used to block molecular effects of JWH-133). Molecular analysis revealed upregulation of Cnr2 transcript (encoding CB2 receptor) after monoiodoacetate treatment that tended to decrease after additional incubation with JWH-133. The researchers also observed cell proliferation caused by monoiodoacetate that could be completely reversed by JWH-133 treatment.
Finally, a scratch-wound was performed to evaluate whether the effect of JWH-133 is CB2-dependent. This was done using AM-630, an antagonist of CB2, which was co-administered with monoiodoacetate and JWH-133. Migration of human chondrocytes significantly decreased after treatment with monoiodoacetate and inhibition was abolished with the administration of JWH-133. Blocking the CB2 receptor impaired the protective effect of JWH-133, leading to the conclusion that the effects induced by JWH-133 are dependent on CB2 receptor activation.
Based on these findings, the authors conclude that there is sufficient evidence to support the potential of CB2-agonists in novel applications aimed at preserving articular cartilage and joint function as opposed to simply alleviating OA symptoms. The researchers suggest that, together with the anti-inflammatory and antinociceptive properties of CB2 agonists, there is a need for further investigations into this novel, innovative dual-acting therapy on OA. Importantly, there have yet to be any in-human studies which have sought to evaluate the effects of these medications on disease progression in OA. These will be integral in determining their efficacy in humans before they can be recommended for this purpose.