Arthritis News – 2003
Do Prostaglandin E2 Receptors contribute to the Pathogenesis of Rheumatoid Arthritis
Rheumatoid arthritis is a chronic inflammatory autoimmune disease that results in the destruction of cartilage and bone. Prostaglandins causing vasodilatation, such as prostaglandin E2 (PGE2), are recognized as important mediators of localized inflammation. Evidence that supports the proinflammatory effects of prostaglandins is the ability of nonsteroidal anti-inflammatory drugs to effectively inhibit prostaglandin synthesis resulting in a decrease in inflammation. The purpose of this study by McCoy et al (J. Clin. Invest. 110:651-658;2002) was to characterize the role of the four known PGE2 receptors EP1, EP2, EP3, and EP4 in the pathogenesis of rheumatoid arthritis (RA) using an experimental murine model of RA.
Methods: An experimental model of RA was generated with collagen antibody induced arthritis (CAIA) in 8 to 10 week old mice genetically deficient in the known four PGE2 receptors EP1–/–, EP2–/–, EP3–/–, EP4–/– and compared to the corresponding genetic wild type controls. Peritoneal macrophage levels of PGE2 and IL-6 and to serum levels of PGE2, IL-6, murine SAA, and type II collagen antibody were quantified by ELISA. EP4 mRNA obtained from liver and macrophages was detected by RT-PCR. Additionally, GADPH and IL-1bmRNA were determined by an ELISA mRNA kit.
Results: The development of CAIA was compared in the 4 EP receptor deficient mice to genetic wild type controls. There was no difference in the course and severity of disease in the EP1, EP2, and EP3 receptor deficient mice in relation to the genetic wild type controls. However, the EP4 receptor deficient mice displayed significant differences in the severity and incidence of disease in comparison to all four genetic wild type controls. The EP4 receptor deficient mice displayed reduced histopathological deterioration to genetic wild type EP4 mice as evident by a significant decrease in the Mankin or overall structure score (11.1 + 0.4 vs. 4.7 + 0.7) and type II collagen breakdown scores (1.8 ++ 0.5 vs. 0.2 + 0.1) in the affected joints. In contrast to the EP4 wild type controls, the EP4 receptor deficient mice demonstrated a significant decrease in structural changes as evident by reduced hyperplasia, pannus formation, surface cartilage destruction, and proteoglycan loss. Additionally, serum and peritoneal exudate levels of serum amyloid A (SAA) and IL-6, inflammatory biomarkers, were reduced in EP4 receptor deficient CAIA mice whereas collagen antibody levels were similar to wild type controls. Furthermore, IL-1bmRNA levels were significantly decreased in the liver specimens of wild type CAIA controls and EP4 receptor deficient CAIA mice.
Conclusion: These studies strongly support the role of EP4 receptors in local and systemic inflammation. These results suggest that PGE2 receptors contribute to the pathogenesis of RA and therefore, PGE2 receptor antagonists may serve as novel therapeutic agents in the treatment of RA.
Editorial Comments: Drugs that block prostaglandin production (nonsteroidal anti-inflammatory agents and COX-2 inhibitors) have long been known to have a beneficial effect in inflammatory diseases like RA. Prostaglandins, particularly PGE2, are highly inflammatory. However, despite the identification of multiple prostaglandin receptors, the one(s) that mediates the inflammatory effects of PGE2 had not been clarified. The current study identified EP4 as that receptor. If confirmed in humans in diseases such as RA, then the development of a selective EP4 blocker would be a logical next step as it might avoid some of the side effects associated with indiscriminate blocking of all or most prostanoids. For example, COX-2 inhibitors may increase the risk of myocardial infarction by inhibiting prostacyclin along with PGE2. This potential untoward side effect could theoretically be avoided by selective targeting and blocking of the relevant PGE receptor subtype.
