Open Access Highly Accessed Research article

Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis

Shin Fukuda1, Hitoshi Kohsaka1, Aiko Takayasu1, Waka Yokoyama1, Chie Miyabe12, Yoshishige Miyabe1, Masayoshi Harigai13, Nobuyuki Miyasaka1 and Toshihiro Nanki134*

Author Affiliations

1 Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, 113-8519 Bunkyo-ku, Tokyo, Japan

2 Department of Dermatology, Tokyo Medical University, 6-1-1 Shinjuku, 160-8402 Shinjuku-ku, Tokyo, Japan

3 Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, 113-8519 Bunkyo-ku, Tokyo, Japan

4 Department of Clinical Research Medicine, Teikyo University, 2-11-1 Kaga, 173-8605 Itabashi-ku, Tokyo, Japan

For all author emails, please log on.

BMC Musculoskeletal Disorders 2014, 15:275  doi:10.1186/1471-2474-15-275

Published: 12 August 2014



Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive. One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells. Theoretically, selective CB2 agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis.


The expression of CB2 was analyzed with immunohistochemistry and Western blotting. Interleukin (IL)-6, matrix metalloproteinase-3 (MMP-3), and chemokine (C-C motif) ligand 2 (CCL2) were quantified with enzyme-linked immunosorbent assays (ELISA). Osteoclastogenesis was assessed with tartrate-resistant acid phosphatase staining and the resorption of coated-calcium phosphate. Effect of JWH133, a selective CB2 agonist, on murine collagen type II (CII)-induced arthritis (CIA) was evaluated with arthritis score, and histological and radiographic changes. IFN-γ and IL-17 production by CII-stimulated splenocytes and serum anti-CII Ab were analyzed by ELISA.


Immunohistochemistry showed that CB2 was expressed more in the synovial tissues from the rheumatoid joints than in those from the osteoarthritis joints. CB2 expression on RA FLS was confirmed with Western blot analysis. JWH133 inhibited IL-6, MMP-3, and CCL2 production from tumor necrosis factor-α-stimulated fibroblast-like synoviocytes (FLS) derived from the rheumatoid joints, and osteoclastogenesis of peripheral blood monocytes. Administration of JWH133 to CIA mice reduced the arthritis score, inflammatory cell infiltration, bone destruction, and anti-CII IgG1 production.


The present study suggests that a selective CB2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.

Cannabinoid; Cannabinoid receptor 2 (CB2); Rheumatoid arthritis; JWH133; Fibroblast-like synoviocyte; Monocyte