Effects Of Targeted Cannabinoid Receptor 2 On Experimental Rheumatoid Arthritis And Mechanism

Objective:To investigate the effects of JWH-133 on rheumatoid arthritis(RA) and its possible mechanism in the experimental collagen-induced arthritis(Cl A) mice.Methods: Arthritis of mice to was induced injecting bovine II collagen to DBA/1 mice。The mice were randomly divided into five groups:normal control group, CIA model group receiving normal saline, low dose(1mg/kg) of JWH-133 treatment group, high dose(10mg/kg) of JWH-133 treatment group and Methotrexate(MTX) treatment group.The body weight,the hind paw thickness,the arthritic index of mice at different time points were observed and measured. The features of the arthritis were evaluated by histological changes and Micro-CT examination.The levels of TNF-a, IL-1b, IL-6, MMP-3, COX-2 and i NOS were detected by immunohistochemical staining. Tartrate-resistant acid-phosphatase(TRAP) staining was used to determine the number of mature osteoclast. Expression of RANKL and OPG was observed by immunohistochemical staining technique.Results:JWH-133(10mg/kg/d) significantly attenuated weight decrease,the hind paw thickness and decreased the arthritis scores in CIA mice.Histological analysis confirmed the suppression of joint inflammation and showed prevention of cartilage and bone destruction after treatment of JWH-133(10mg/kg/d).The results of Micro-CT imaging analysis showed that treatment with JWH-133(10mg/kg) significantly preserve bone volume and integrity in CIA mice.The over-production of TNF-a, IL-1b, IL-6, MMP-3, COX-2 and i NOS was significantly reduced after treatment of 10mg/kg/d JWH-133. There was a reduction in the number of TRAP positive cells in high dose of JWH-133 treatment group compared with CIA model group. RANKL positive was found in many cells in bone erosion areas in CIA group. The level of expression of RANKL in cartilage and bone was higher in CIA group than that of control group.The expression of RANKL in high dose(10mg/kg) of JWH-133 treatment group was lower than CIA model group whereas the OPG expression was higher.Conclusions:JWH-133 suppresses the symptoms of polyarthritis of CIA mice,suggesting that JWH-133 has an anti-inflammatory effect on RA. Its mechanism may be related to the modification of the abnormal immunological function of CIA mice, and reduction of inflammatory cytokines. JWH-133 may play an important role in osteocalstogenesis and bone destruction in RA by up-regulating the expression of RANKL and down-regulating that of OPG.