title: Tenidap reduces the level of interleukin 1 receptors and collagenase expression in human arthritic synovial fibroblasts.
abstract: OBJECTIVE
  To investigate the effects of tenidap, a new antirheumatic drug, sodium diclofenac, a non-steroidal antiinflammatory drug, and a disease modifying antirheumatic drug, hydroxychloroquine, on the level and expression of interleukin 1 receptors (IL-1R) on synovial fibroblasts from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, the effect of tenidap on IL-1 stimulated collagenase gene expression was studied.
  
  
  METHODS
  Binding assays were performed using [125I]-IL-1 beta as radioligand. Flow cytometry was done using a specific antibody against type I IL-1R. Protein synthesis was determined by [3H]-leucine incorporation. Levels of expression were determined by Northern Blot for collagenase and by reverse transcription polymerase chain reaction (RT-PCR) for type I IL-1R.
  
  
  RESULTS
  Tenidap produced for both OA and RA synovial fibroblasts a dose dependent decrease in the number of IL-1 binding sites/cell. A reduction of 41% (2.5 micrograms/ml) to 81% (at therapeutic concentration, 20 micrograms/ml) was noted for OA, while 29% (2.5 micrograms/ml) to 89% (20 micrograms/ml) was found for RA cells. Diclofenac produced no effect on OA cells, and minimal inhibition of RA synovial fibroblasts was observed only at pharmacological concentration (12%, 300 mg/ml). Hydroxychloroquine had effects similar to diclofenac. The decreased number of IL-1 binding sites/cell by tenidap was time dependent and reached 93% inhibition after 48 h. The effect of tenidap appears to be posttranscriptional, judged by the marked reduction of the type I IL-1R protein/cell and the absence of effect on its mRNA level. Tenidap also markedly reduced the IL-1 induced collagenase expression in synovial fibroblasts.
  
  
  CONCLUSIONS
  At therapeutic concentrations tenidap is a potent inhibitor of type I IL-1R in OA and RA synovial fibroblasts. The effect of tenidap was considerably more marked than diclofenac or hydroxychloroquine.
authors.affiliation: Department of Medicine, University of Montreal, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Martel-Pelletier
authors.forename: F
authors.initials: F
authors.lastname: Mineau
authors.forename: G
authors.initials: G
authors.lastname: Tardif
authors.forename: J C
authors.initials: JC
authors.lastname: Fernandes
authors.forename: P
authors.initials: P
authors.lastname: Ranger
authors.forename: L
authors.initials: L
authors.lastname: Loose
authors.forename: J P
authors.initials: JP
authors.lastname: Pelletier
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D015152:Blotting, Northern; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis / Q000187:drug effects*; D004008:Diclofenac / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D005434:Flow Cytometry; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism; D000078183:Oxindoles; D016133:Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000187:drug effects*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D000078183:Oxindoles; D017472:Receptors, Interleukin-1; D004008:Diclofenac; D006886:Hydroxychloroquine; C062866:tenidap; D017364:Collagenases