Hypoxia-Induced Endogenous Prostaglandin E2 Negatively Regulates Hypoxia-Enhanced Aberrant Overgrowth of Rheumatoid Synovial Tissue

Hirofumi Mitomi¹, Hidehiro Yamada¹, Toshiko Nozaki Shibata¹, Hiroshi Ito¹, Yoshioki Yamasaki², So Nomoto³, Atsushi Kusaba⁴, Hiroki Yamashita⁴ and Shoichi Ozaki¹, ¹Internal Medicine, St. Marianna University, Kawasaki, Japan, ²Medicine, St. Marianna University, Kawasaki, Japan, ³Department of Orthopedic Surgery and Rheumatology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan, ⁴Institute of Rheumatology, Ebina General Hospital, Ebina, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Nonsteroidal antiinflammatory drugs (NSAIDs), prostaglandins, rheumatoid arthritis (RA) and synovial cells, synovial fluid

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenisis

Session Type: Abstract Submissions (ACR)

Background/Purpose: 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 (ELISA) 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 TNF-alpha (TNF-α), macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-9 (MMP-9) under periodic hypoxia compared to normoxia. 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.

Conclusion: The enhancing effect of periodic hypoxia on the aberrant overgrowth of rheumatoid synovial tissue was effectively down-regulated by the simultaneously induced endogenous PGE2. It is suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) enhances hypoxia-induced synovial overgrowth in rheumatoid arthritis.

Disclosure:

H. Mitomi,
None;

H. Yamada,
None;

T. Nozaki Shibata,
None;

H. Ito,
None;

Y. Yamasaki,
None;

S. Nomoto,
None;

A. Kusaba,
None;

H. Yamashita,
None;

S. Ozaki,
None.

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