title: Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis.
abstract: OBJECTIVE
  Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which is devoid of psychoactivity. We have demonstrated the expression of CB2R in synovial tissue from patients with rheumatoid arthritis (RA), and its specific activation shows inhibitory effects on fibroblast-like synoviocytes. However, it is still unclear whether selective activation of CB2R inhibits joint inflammation or protects joint damage in RA.
  
  
  METHODS
  A murine model of collagen-induced arthritis (CIA) was used to evaluate the therapeutic efficacy of HU-308, a selective CB2R agonist. The disease severity was evaluated by semi-quantitative scoring of joint swelling, histological assessment of joint inflammation and structure, and radiographic assessment of joint destruction by using digital plain radiographs and micro-CT scans. The concentrations of various isotypes of anti-collagen II antibodies in sera and the levels of cytokines in culture supernatants were determined by ELISA.
  
  
  RESULTS
  Compared with vehicle treatment, protective treatment with intraperitoneal injection of HU-308 (0.3-1.0 mg/kg) failed to decrease the incidence of the development of CIA, but it effectively suppressed the severity of the disease. In CIA mice, treatment with HU-308 significantly decreased joint swelling, synovial inflammation, and joint destruction, as well as serum levels of anti-collagen II antibodies. In vitro, HU-308 (1-10 μM) significantly suppressed the production of proinflammatory cytokines IL-6 and TNF-α from lipopolysaccharide-stimulated murine peritoneal macrophages with intact CB2R in dose-dependent manners. HU-308 failed to elicit any inhibitory effect of on lipopolysaccharide-stimulated macrophages from CB2R-knockout mice.
  
  
  CONCLUSIONS
  Activation of CB2R by HU-308 has therapeutic potential for RA to suppress synovitis and alleviate joint destruction by inhibiting the production of autoantibodies and proinflammatory cytokines.
authors.affiliation: Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, Shanghai, China; Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China; Department of Pharmacy, Children's Hospital Affiliated to Soochow University, Suzhou, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Gui
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China. Electronic address: dfsu2008@gmail.com.
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.affiliation: Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, Shanghai, China. Electronic address: dsm@medmail.com.cn.
authors.forename: Sheng-Ming
authors.initials: SM
authors.lastname: Dai
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology; D003094:Collagen / Q000276:immunology; D003175:Complement C2 / Q000276:immunology; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000096:biosynthesis; D007596:Joints / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D012720:Severity of Illness Index; D013585:Synovitis / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D055114:X-Ray Microtomography
chemical_list: D001323:Autoantibodies; D002186:Cannabinoids; D003175:Complement C2; D015850:Interleukin-6; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; C402416:HU 308; D003094:Collagen
keywords: Cannabinoid receptor 2; Collagen-induced arthritis; Rheumatoid arthritis