title: Kappa and delta opioid receptors are expressed but down-regulated in fibroblast-like synoviocytes of patients with rheumatoid arthritis and osteoarthritis.
abstract: OBJECTIVE
  To investigate the expression and regulation of the kappa-opioid receptor (KOR) and the delta-opioid receptor (DOR) in fibroblast-like synoviocytes (FLS) from patients with osteoarthritis (OA) and rheumatoid arthritis (RA), and to explore the potential antiarthritic mechanisms of peripheral KORs.
  
  
  METHODS
  FLS isolated from synovial tissues of 6 OA patients, 8 RA patients, and 2 healthy individuals were exposed to the selective KOR agonist U69593, the selective DOR agonist SNC 80, and kappa-opioid dynorphin A in the presence or absence of the KOR antagonist nor-binaltorphimine, the DOR antagonist naltrindole, and the proinflammatory cytokines tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta). The expression of KOR and DOR in OA and RA FLS was evaluated on the messenger RNA (mRNA) and protein levels with TaqMan real-time reverse transcriptase-polymerase chain reaction and immunofluorescence staining, respectively. KOR/DOR-mediated activation of ERK-1 and ERK-2 was investigated by Western blotting.
  
  
  RESULTS
  We detected functional KOR and DOR in normal FLS and observed a reduction of both receptors in OA and RA FLS, which was more distinct in RA FLS. U69593 enhanced KOR mRNA expression in both OA and RA FLS in a KOR antagonist-reversible manner. However, the dose required for maximal enhancement in RA FLS was 10 times higher than that required in OA FLS. TNFalpha and IL-1beta both suppressed the expression of DOR and KOR mRNA in both OA and RA FLS.
  
  
  CONCLUSIONS
  DOR and KOR are constitutively present in normal FLS and are suppressed under inflammatory conditions, such as RA and OA. Most interestingly, the KOR agonist U69593 may exert an antiarthritic effect via up-regulation of KOR in OA and RA FLS.
authors.affiliation: University Hospital Zurich, Zurich, Switzerland.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.forename: André
authors.initials: A
authors.lastname: Aeschlimann
authors.forename: Natasa
authors.initials: N
authors.lastname: Reisch
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Beat R
authors.initials: BR
authors.lastname: Simmen
authors.forename: Beat A
authors.initials: BA
authors.lastname: Michel
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Haiko
authors.initials: H
authors.lastname: Sprott
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D010003:Osteoarthritis / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000096:biosynthesis*; D017473:Receptors, Opioid, kappa / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D007375:Interleukin-1; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D014409:Tumor Necrosis Factor-alpha