No abstract

Osteoarthritis (OA) is a multifactorial disease associated with pathological changes in a wide variety of musculoskeletal tissues, including articular cartilage degeneration, synovitis, ligament tears as well as muscle wasting. Cartilage is known as a predominant pathology, however the association between the pathogenesis of OA around the knee joint tissues and pain is limited. Infrapatellar fat pad (IFP) fibrosis and muscle atrophy are the main features of chronic OA phenomenon that cause joint pain, stiffness and impairment of skeletal muscle, which contributing to locomotor restriction in OA patients. Despite a high prevalence of knee OA, there is still a lack of comprehensive information explaining the interplaying mechanisms among these OA features. Although various animal models of OA have been characterized, none of them can truly represent all aspects of the OA features. Monoiodoacetate (MIA)‐induced OA is one of the most common animal model used in the OA research, in which intra‐articular injection of MIA can lead to articular cartilage destruction and development of pain‐like behaviour. This study aimed to characterize and determine the suitable time point, at which MIA could significantly induce the development of IFP fibrosis and hind limb muscle atrophy in this OA rat model. IFP and soleus muscle were collected for histological analysis at 4 and 8 weeks post‐OA induction. In addition, pain‐related behavior was also evaluated using hind limb weight distribution test. Semi‐quantitative analysis of Masson’s trichrome staining revealed that the percentage of IFP fibrosis area was not significantly different at 4 weeks compared to 8 weeks post‐OA induction. In addition, there was a significant (p<0.05) reduction of soleus muscle fiber cross‐sectional area at 4 and 8 weeks of OA‐induced groups compared to their relative controls; however, the muscle fiber atrophy was more pronounced at 4 weeks compared to 8 weeks. Moreover, there was a significant reduction in the mean values of percent weight borne on the injured hind limb for the OA‐induced group compared to the saline group throughout the study period (p<0.05). Interestingly, pain response significantly reversed at 8 weeks compared to 4 weeks (p<0.001), suggesting that this reversal in pain response could be the contributing factor on alleviation of soleus muscle atrophy under chronic OA pain. These results suggested that at 4 weeks post‐MIA injection is sufficient and suitable period to investigate OA‐related pain, IFP fibrosis and muscle atrophy. Taken together, a MIA‐induced OA rat can be used as a representative model in translational research to understand IFP fibrosis and hind limb muscle atrophy in OA as an integrated musculoskeletal disease.

Currently, there are no approved disease‐modifying drugs for osteoarthritis (OA). OA patients depend upon analgesic drugs such as nonsteroidal anti‐inflammatory drugs (NSAIDs) and opioid analgesics for pain management. Despite existing therapies, pain relief in OA remains largely inadequate. Recently, the functional role for TRPA1 receptor‐channels which are expressed on nociceptor sensory nerves and other non‐neuronal cells within the joint has been identified, although studies of the role of TRPA1 in the pathogenesis of OA pain are limited. TRPA1 represents a promising target for the development of novel therapeutic agent for managing OA pain. This study investigated the effects of ALGX‐XC20, a highly selective and potent TRPA1 antagonist with a long in‐vivo half‐life on pain behaviors and cartilage damage in a rat model of monosodium iodoacetate (MIA)‐induced OA. The analgesic effect of a single dose (30 mg/kg; oral) of ALGX‐XC20 was evaluated for a period of 14 days post‐OA induction and compared to celecoxib (30 mg/kg; oral), a selective cyclooxygenase‐2 (COX‐2) inhibitor by using pain‐related behavior assessments, including hindlimb weight distribution and von Frey tests. The histological scoring of cartilage damage was also determined according to the Mankin grading system. The MIA‐induced OA rat group displayed a large reduction in the weight bearing distribution on the ipsilateral hindlimb (p<0.01–0.05) and hind paw mechanical withdrawal thresholds compared to saline control group, which was maintained for 14 days. The MIA‐evoked reduction in weight bearing distribution was significantly reversed (~50%) in the MIA‐induced group treated with ALGX‐XC20 compared to the MIA‐treated group for the 2‐week duration, while the antiallodynic effect of ALGX‐XC20 was less pronounced. In addition, histopathology studies showed that ALGX‐XC20 was also effective in reducing the severe cartilage damage in the MIA‐injected knee joint as shown by a significant improvement in the Mankin score in the ALGX‐XC20 treated group at 14 days (p<0.05). The magnitude of the effect on spontaneous weight bearing behavior due to ALGX‐XC20 treatment is closely comparable to the effects observed for the MIA‐celecoxib group and reported for TRPA1‐KO animals. The positive analgesic effects in this OA model due to pharmacological inhibition of TRPA1 by ALGX‐XC20 occur without any adverse behavioral effects. These in vivo data suggest that ALGX‐XC20 may be used as a novel therapeutic analgesic/anti‐inflammatory drug for the treatment of chronic arthritis, such as OA pain. This TRPA1 antagonist drug may also represent a new class of disease‐modifying drug by providing a chondroprotective effect on articular cartilage.