title: Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis.
abstract: BACKGROUND
  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 (CB(2)) is expressed primarily by immune cells. Theoretically, selective CB(2) agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB(2) agonist on arthritis.
  
  
  METHODS
  The expression of CB(2) 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 CB(2) 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.
  
  
  RESULTS
  Immunohistochemistry showed that CB(2) was expressed more in the synovial tissues from the rheumatoid joints than in those from the osteoarthritis joints. CB(2) 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.
  
  
  CONCLUSIONS
  The present study suggests that a selective CB(2) agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.
authors.forename: Shin
authors.initials: S
authors.lastname: Fukuda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohsaka
authors.forename: Aiko
authors.initials: A
authors.lastname: Takayasu
authors.forename: Waka
authors.initials: W
authors.lastname: Yokoyama
authors.forename: Chie
authors.initials: C
authors.lastname: Miyabe
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Miyabe
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Harigai
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.affiliation: 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. nanki@med.teikyo-u.ac.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D002186:Cannabinoids / Q000008:administration & dosage*; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism
chemical_list: C588309:CNR2 protein, human; D002186:Cannabinoids; D043885:Receptor, Cannabinoid, CB2; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC