Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis

Immunobiology. 2015 Jun;220(6):817-22. doi: 10.1016/j.imbio.2014.12.012. Epub 2014 Dec 30.


Objectives: 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.

Keywords: Cannabinoid receptor 2; Collagen-induced arthritis; Rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / diagnosis
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / metabolism*
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Cannabinoids / administration & dosage
  • Cannabinoids / pharmacology
  • Collagen / immunology
  • Complement C2 / immunology
  • Disease Models, Animal
  • Interleukin-6 / biosynthesis
  • Joints / immunology*
  • Joints / metabolism*
  • Joints / pathology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Severity of Illness Index
  • Synovitis / immunology*
  • Synovitis / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • X-Ray Microtomography


  • Autoantibodies
  • Cannabinoids
  • Complement C2
  • Interleukin-6
  • Receptor, Cannabinoid, CB2
  • Tumor Necrosis Factor-alpha
  • HU 308
  • Collagen