The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to bone and cartilage destruction. A substantial body of evidence suggests that prostaglandin E2 (PGE2) contributes to the pathogenesis of RA, and nonsteroidal anti-inflammatory drugs, inhibitors of the synthesis of PGE2 and other prostanoids, continue to be used in the treatment of this disease. To begin to understand the mechanism by which prostaglandins modulate the pathophysiology of this disease, we examined mice lacking each of the four known PGE2 (EP) receptors after generation of collagen antibody-induced arthritis, an animal model of RA. Homozygous deletion of the EP1, EP2, or EP3 receptors did not affect the development of arthritis, whereas EP4 receptor-deficient mice showed decreased incidence and severity of disease. These animals also showed reduced inflammation as assessed by circulating IL-6 and serum amyloid A levels. Joint histopathology of EP4(-/-) animals revealed reduced bone destruction, proteoglycan loss, and type II collagen breakdown in cartilage compared with EP4(+/+) mice. Furthermore, liver and macrophages isolated from EP4(-/-) animals produced significantly less IL-1 beta and IL-6 than control samples. Thus, PGE2 contributes to disease progression at least in part by binding to the EP4 receptor. Antagonists of this receptor might therefore provide novel agents for the treatment of RA.
Pfizer Global Research and Development, Department of Inflammation and Pathology, Groton, Connecticut 06340, USA.
Jennifer M
JM
McCoy
Joan R
JR
Wicks
Laurent P
LP
Audoly
D000818:Animals; D001168:Arthritis / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D018450:Disease Progression; D017353:Gene Deletion; D006720:Homozygote; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics* / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013997:Time Factors
D007375:Interleukin-1; D015850:Interleukin-6; C545651:Ptger4 protein, mouse; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000685:Serum Amyloid A Protein