New therapeutic approach for rheumatoid arthritis by targeting the intracellular molecule.

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We found that some conventional nonsteroidal anti-inflammatory drugs(NSAIDs) such as indometacin and diclofenac induced apoptosis in rheumatoid synovial fibroblasts (J Pharmacol Exp Ther 2002;302:18). We also found that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, exert pro-apoptotic effect on rheumatoid synovial fibroblasts (Arthritis Rheum 2002;46:3159) and colon cancer cell lines (FEBS Lett 2002;531:278) by COX-independent mechanisms. In addition, high concentration of aspirin and salicylate (J Pharm Pharmacol 2002;54:1675), and triptolide, an active compound identified in a traditional Chinese herb (BMC Pharmacol 2002;4:2), induce apoptosis in rheumatoid synovial cells. From these finding, we hypothesized that some intracellular molecules play an important role in inducing apoptosis by these anti-inflammatory agents. During the research procedure, we invented a novel potent pro-apoptotic agent derived from celecoxib. We are now trying to find the targeting molecule to i … More nduce apoptosis. Concerning arachidonic acid cascade, recent studies revealed that not only COX but also terminal enzymes such as prostaglandin E synthase(PGES) are important in the understanding of the pathogenesis of inflammation and mechanisms of action of NSAIDs. PGES is a recently identified terminal enzyme that acts downstream of COX and catalyzes the conversion of prostaglandin(PG) H2 to PGE2. At least three isozymes have been cloned so far, which are called membrane-associated PGES(mPGES)-1,mPGES-2,and cytosolic PGES. Induction of mPGES-1 in the component of articular tissues of patients with rheumatoid arthritis and osteoarthritis has been demonstrated in vitro by us (J Rheumatol 2002;29:1836 & Arthritis Res Ther 2004;6:R355). We then showed that PGE2 is an enhancer for interleukin-16-induced expression of mPGES-1 in rheumatoid synovial fibroblasts (Arthritis Rheum 2003;48:2819). These findings suggest that mPGES-1 may be a novel therapeutic target for arthritis. PGD synthase(PGDS) is an enzyme to produce an intrinsic pro-apoptotic PG (15-deoxy-Δ^<12,14>-PGJ2). We also found the anti-inflammatory effects of the retrovirally transfected PGDS-expressing fibroblasts in bleomycin-induced lung injury (Am J Respir Cell Mol Biol 2003;28:582) and monosodium urate monohydrate crystal-induced acute inflammation (Arthritis Rheum 2003;48:2931) in animal models. PGDS or 15-deoxy-Δ^<12,14>-PGJ2 will possibly be another target molecule for the novel therapy for rheumatoid arthritis and other rheumatic diseases. Less