Vol.23 No.6

Original Article

Hypoxia-induced endogenous prostaglandin E2 negatively regulates hypoxia-enhanced aberrant overgrowth of rheumatoid synovial tissue

Authors

Hirofumi Mitomi1 , Hidehiro Yamada1 , Hiroshi Ito1 , Toshiko Nozaki Shibata1 , Yoshioki Yamasaki 1 , So Nomoto2 , Atsushi Kusaba3 , Hiroki Yamashita3 , Shoichi Ozaki1

  • 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
  • Department of Orthopedic Surgery and Rheumatology, Saiseikai Yokohamashi Tobu Hospital, 3-6-1, Shimosueyoshi, Tsurumi-ku, Yokohama 230-8765, Japan
  • Institute of Rheumatology, Ebina General Hospital, 1320, Kawaraguchi, Ebina 243-0433, Japan
Received:

3 August 2012

Accepted:

26 October 2012

Published online:

25 November 2012

Full Text

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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 enzymelinked 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-a (TNF-a), 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.

Key words

Rheumatoid arthritis, Hypoxia, Synovial overgrowth, PGE2, NSAIDs