Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis

Rheumatology (Oxford). 2014 May;53(5):802-9. doi: 10.1093/rheumatology/ket447. Epub 2014 Jan 17.


Objective: Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which shows no psychoactivity. However, it is still unclear whether CB2R is expressed in fibroblast-like synoviocytes (FLS) of RA. In this study we investigated whether CB2R is expressed in FLS of RA, and whether CB2R activation modulates the function of RA-FLS.

Methods: Expression of CB2R in synovial tissue and FLS was studied by immunohistochemistry, western blotting and RT-PCR. mRNA expression levels of CB2R, IL-6 and MMPs were analysed by quantitative real-time RT-PCR. The protein concentrations of IL-6 and MMPs in culture supernatants were determined by ELISA. The protein levels of signal transducing molecules were assayed by western blotting.

Results: Both mRNA and protein expression of CB2R were found in synovial tissue and cultured FLS with slightly higher levels in RA patients than in OA patients. In cultured RA-FLS, the expression level of CB2R was up-regulated by stimulation with IL-1β, TNF-α or lipopolysaccharide. In vitro, HU-308, a selective CB2R agonist, inhibited IL-1β-induced proliferation of RA-FLS as well as IL-1β-induced production of MMP-3, MMP-13 and IL-6 in RA-FLS in a dose-dependent manner. HU-308 also suppressed IL-1β-induced activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in FLS.

Conclusion: In RA-FLS, proinflammatory mediators up-regulate the expression of CB2R, which negatively regulates the production of proinflammatory cytokines and MMPs. These data suggest that CB2R may be a potential therapeutic target of RA.

Keywords: cannabinoid receptor 2; fibroblast-like synoviocytes; interleukin 6; matrix metalloproteinases; rheumatoid arthritis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Cannabinoids / pharmacology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • In Vitro Techniques
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism*
  • Matrix Metalloproteinases / metabolism*
  • Middle Aged
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • CNR2 protein, human
  • Cannabinoids
  • Interleukin-1beta
  • Interleukin-6
  • Receptor, Cannabinoid, CB2
  • HU 308
  • Matrix Metalloproteinases