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

Abstract

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.

• Authors: Huan Gui, Xia Liu, Li-Rong Liu, Ding-Feng Su, Sheng-Ming Dai
• Journal: Immunobiology (Immunobiology) Vol. 220 Issue 6 Pg. 817-22 (Jun 2015) ISSN: 1878-3279 [Electronic] Netherlands
• PMID: 25601571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier GmbH. All rights reserved.

Chemical References

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

Topics

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