title: Hypoxia-induced endogenous prostaglandin E2 negatively regulates hypoxia-enhanced aberrant overgrowth of rheumatoid synovial tissue.
abstract: OBJECTIVE
  During isometric exercise, the synovial joint tissue is prone to hypoxia, which is further enhanced in the presence of synovial inflammation. Hypoxia is also known to induce inflammatory cascades, suggesting that periodic hypoxia perpetuates synovitis in rheumatoid arthritis. We previously established an ex vivo cellular model of rheumatoid arthritis using the synovial tissue-derived inflammatory cells, which reproduced aberrant synovial overgrowth and pannus-like tissue development in vitro. Using this model, we investigated the regulatory mechanism of synovial cells against hypoxia in rheumatoid arthritis.
  
  
  METHODS
  Inflammatory cells that infiltrated synovial tissue from patients with rheumatoid arthritis were collected without enzyme digestion, and designated as synovial tissue-derived inflammatory cells. Under normoxia or periodic hypoxia twice a week, their single-cell suspension was cultured in medium alone to observe an aberrant overgrowth of inflammatory tissue in vitro. Cytokines produced in the culture supernatants were measured by enzyme-linked immunosorbent assay kits.
  
  
  RESULTS
  Primary culture of the synovial tissue-derived inflammatory cells under periodic hypoxia resulted in the attenuation of the spontaneous growth of inflammatory tissue in vitro compared to the culture under normoxia. Endogenous prostaglandin E2 (PGE2) production was enhanced under periodic hypoxia. When endogenous PGE2 was blocked by indomethacin, the aberrant tissue overgrowth was more enhanced under hypoxia than normoxia. Indomethacin also enhanced the production of tumor necrosis factor-α (TNF-α), macrophage colony-stimulating factor (M-CSF), and matrix metalloproteinase-9 (MMP-9) under periodic hypoxia compared to normoxia. The EP4-specific antagonist reproduced the effect of indomethacin. Exogenous PGE1 and EP4-specific agonist effectively inhibited the aberrant overgrowth and the production of the inflammatory mediators under periodic hypoxia as well as normoxia.
  
  
  CONCLUSIONS
  The enhancing effect of periodic hypoxia on the aberrant overgrowth of rheumatoid synovial tissue was effectively down-regulated by the simultaneously induced endogenous PGE2.
authors.affiliation: Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 216-8511, Japan, mitomihirofumi@marianna-u.ac.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mitomi
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Yamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Toshiko
authors.initials: T
authors.lastname: Nozaki Shibata
authors.forename: Yoshioki
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: So
authors.initials: S
authors.lastname: Nomoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kusaba
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamashita
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ozaki
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D007213:Indomethacin / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone; D007213:Indomethacin