title: Role of PGE2 and EP receptors in the pathogenesis of rheumatoid arthritis and as a novel therapeutic strategy.
abstract: Recent progress in understanding the pathogenesis of rheumatoid arthritis (RA) in parallel with elucidation of the functional role of the prostaglandin receptor subfamily has revealed an important regulatory role of PGE2, in addition to its well-known proinflammatory role in the progression of RA. Characteristic features of RA are synovial proliferation and pannus formation, which result in the destruction of cartilage and bone. Pannus tissue is mainly composed of macrophages and fibroblast-like synoviocytes. Both T cell-derived IL-17 and macrophage-derived TNF-alpha seem to play a central role in the progression of proinflammatory cascades in RA. PGE2 is also produced in response to proinflammatory cytokines, which in turn negatively regulates both IL-17 and TNF-alpha expression and TNF/IL-1-induced activation of fibroblast-like synoviocytes through EP2/EP4 receptors, resulting in the modulation of proinflammatory cascades. IL-17- and TNF-activated macrophages differentiate into osteoclasts in the presence of M-CSF and RANKL expressed by fibroblast-like synoviocytes. PGE2 binding to EP4 stimulates osteoclastogenesis through enhancing RANKL expression. At the same time, PGE2 suppresses osteoclastogenesis by inhibiting M-CSF expression of fibroblast-like synoviocytes as well as both IL-17 and IL-17-induced TNF-alpha expression of macrophages. PGE2-EP4 also activates osteoblastogenesis through increasing cbfa1 and osterix, two essential transcription factors required for bone formation. The net effect of PGE2 may direct toward repair of eroding bone through the suppression of inflammation and enhancement of bone remodeling. Here, we discuss a diverse action of PGE2/EP receptors and their important regulatory roles in the pathogenesis of RA, which may lead to a novel therapeutic strategy.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, St. Marianna Medical School, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Akaogi
authors.forename: Toshiko
authors.initials: T
authors.lastname: Nozaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology*; D016723:Bone Remodeling / Q000187:drug effects; D015232:Dinoprostone / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000502:physiology*
chemical_list: D018501:Antirheumatic Agents; D018836:Inflammation Mediators; D011982:Receptors, Prostaglandin; D015232:Dinoprostone