title: Endogenous prostaglandin E2 inhibits aberrant overgrowth of rheumatoid synovial tissue and the development of osteoclast activity through EP4 receptor.
abstract: OBJECTIVE
  We recently developed an ex vivo cellular model of pannus, the aberrant overgrowth of human synovial tissue. This study was undertaken to use that model to investigate the role of prostaglandin E2 (PGE2) and its receptor subtypes in the development of pannus growth and osteoclast activity in rheumatoid arthritis (RA).
  
  
  METHODS
  Inflammatory cells that infiltrated pannus from patients with RA were collected without enzyme digestion and designated synovial tissue-derived inflammatory cells. Their single-cell suspensions were cultured in medium alone to observe an aberrant overgrowth of inflammatory tissue in vitro. Levels of cytokines produced in culture supernatants were measured using enzyme-linked immunosorbent assay kits. Osteoclast activity was assessed by the development of resorption pits in calcium phosphate-coated slides.
  
  
  RESULTS
  Primary culture of the synovial tissue-derived inflammatory cells resulted in spontaneous reconstruction of inflammatory tissue in vitro within 4 weeks, during which tumor necrosis factor α, PGE2, macrophage colony-stimulating factor, and matrix metalloproteinase 9 were produced in the supernatant. This aberrant overgrowth was inhibited by antirheumatic drugs including methotrexate and infliximab. On calcium phosphate-coated slides, synovial tissue-derived inflammatory cells showed numerous resorption pits. In the presence of inhibitors of endogenous prostanoid production such as indomethacin and NS398, exogenous PGE1 and EP4-specific agonists significantly inhibited all these activities of synovial tissue-derived inflammatory cells in a dose-dependent manner. Addition of indomethacin, NS398, or EP4-specific antagonist resulted in the enhancement of these cells' activities. EP2-specific agonist had a partial effect, while EP1- and EP3-specific agonists had no significant effects.
  
  
  CONCLUSIONS
  These results suggest that endogenous PGE2 produced in rheumatoid synovium negatively regulates aberrant synovial overgrowth and the development of osteoclast activity via EP4.
authors: Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors: Toshiko
authors: T
authors: Shibata-Nozaki
authors: Hiroshi
authors: H
authors: Ito
authors: Hirofumi
authors: H
authors: Mitomi
authors: Jun
authors: J
authors: Akaogi
authors: Tatsuya
authors: T
authors: Komagata
authors: Toshiya
authors: T
authors: Kanaji
authors: Takayuki
authors: T
authors: Maruyama
authors: Toshihito
authors: T
authors: Mori
authors: So
authors: S
authors: Nomoto
authors: Shoichi
authors: S
authors: Ozaki
authors: Hidehiro
authors: H
authors: Yamada
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015232:Dinoprostone; D007213:Indomethacin