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 E 2 (PGE 2 ) 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 tissuederived inflammatory cells resulted in spontaneous reconstruction of inflammatory tissue in vitro within 4 weeks, during which tumor necrosis factor ␣, PGE 2 , 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 PGE 1 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.Conclusion. These results suggest that endogenous PGE 2 produced in rheumatoid synovium negatively regulates aberrant synovial overgrowth and the development of osteoclast activity via EP4.Rheumatoid arthritis (RA) is a progressive, systemic inflammatory disorder that is characterized by a chronic synovitis which leads to pannus formation and joint destruction. Pannus tissue is composed mainly of activated macrophages, T cells, and proliferating fibroblast-like synoviocytes (FLS) (1-3). Both cytokine networks and cell-cell interaction contribute to the development of pannus tissue. Previous studies indicated that both peripheral blood and synovial monocyte/ macrophages had the ability to serve as osteoclast precursors and developed osteoclastic activity when cocultured with either CD14Ϫ synovial cells or FLS in the presence of macrophage colony-stimulating factor (M-CSF) (4). Cultured synovial fibroblasts and mesen-

Antiinflammatory effects of essential oil from the leaves of Cinnamomum cassia and cinnamaldehyde on lipopolysaccharide-stimulated J774A.1 cells

“…[13] Expression of these enzymes is known to be induced by bacterial products, pro-inflammatory cytokines TNF-α and IL-1β and up regulation of them was detected in many chronic inflammatory diseases. [141516] mPGES-1 is recently expected to be a novel therapeutic target for inhibiting inflammatory diseases due to the cardiovascular side effects of selective COX-2 inhibitors. [1718] CO and cinnamaldehyde similarly and significantly inhibited COX-2 and mPGES-1 mRNA expression in LPS-stimulated J774A.1 cells.…”

Anti-inflammatory properties of prostaglandin E2: Deletion of microsomal prostaglandin E synthase-1 exacerbates non-immune inflammatory arthritis in mice

“…Prostanoids and particularly PGE2 have often been viewed as simply proinflammatory mediators in arthritis (7–10). This is somewhat surprising because an important role of PGE2 in the resolution of inflammation where it switches ARA metabolism toward production of anti-inflammatory and pro-resolving lipoxins, resolvins, and protectins is well established (25).…”

“…Prostanoids and PGE2 in particular, have been shown to play an important role in as mediators of symptoms of inflammatory arthritidies including rheumatoid arthritis (RA) as demonstrated by the widespread use of treatments that inhibit PG production (7–10). However, the current strategies to inhibit PGs by using non-steroidal anti-inflammatory drugs (NSAID) and selective COX-2 inhibitors are often inadequate in providing symptomatic relief of pain, swelling, and stiffness (11,12).…”

E-type prostanoid receptor 4 (EP4) in disease and therapy

“…In an ex vivo model of human pannus formation, i.e. aberrant proliferation of synovial tissue leading to joint destruction, endogenous PGE 2 via activating its EP4 receptor, inhibited pannus growth and osteoclast activity (Shibata-Nozaki et al, 2011). These findings might be consistent with a crucial role of EP4 receptors in promoting acute inflammatory responses and pain in arthritis, but also with limiting cartilage and bone destruction in the chronic phase.…”