Abstract
Synovial hyperplasia in rheumatoid arthritis (RA) has been associated with apoptosis deficiency of RA fibroblast-like synoviocytes (FLSs). Celecoxib is a non-steroidal anti-inflammatory drug that has been demonstrated to induce apoptosis in some cellular systems. We have therefore examined the dose- and time-dependent effects of celecoxib on RA FLS viability. Treatment of RA FLSs with celecoxib for 24 hours reduced their viability in a dose-dependent manner. Analysis of celecoxib-treated RA FLSs for their content of apoptotic and necrotic cells by Annexin V staining and TO-PRO-3 uptake displayed only few apoptotic cells. Caspase 3, a key mediator of apoptosis, was not activated in celecoxib-treated RA FLSs, and the presence of specific caspase 3 or pan-caspase inhibitors did not affect celecoxib-induced cell death. Moreover, we could not detect other signs of apoptosis, such as cleavage of poly(ADP-ribose) polymerase, caspase 8 or 9, or DNA fragmentation. We therefore conclude that apoptosis is not the major death pathway in celecoxib-treated RA FLSs.
Highlights
Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid to prostanoids, which mediate mitogenesis, apoptosis, angiogenesis, blood flow, secondary injury, and inflammation [1]
Celecoxib decreases cell activity and proliferation of rheumatoid arthritis fibroblast-like synoviocytes We first analyzed the effect of celecoxib on metabolic activity of RA FLSs
Celecoxib reduces viability and proliferation of synovial fibroblasts extracted from patients with rheumatoid arthritis (RA). (a) Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured for 24 hours in the presence of the cyclooxygenase inhibitors celecoxib, valdecoxib, or indomethacin at the indicated concentrations
Summary
Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid to prostanoids, which mediate mitogenesis, apoptosis, angiogenesis, blood flow, secondary injury (lipid peroxidation and oxidative stress), and inflammation [1]. The COX-1 isoform is constitutively expressed under physiological conditions, whereas expression of the COX-2 isoform is inducible under pathophysiological, mainly inflammatory, conditions [2]. Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of joints, leading to a progressive and irreversible joint destruction [3,4]. The aggressive front of synovial tissue, called pannus, invades and destroys the local articular structure [3,4]. The pannus is characterized by a synovial hyperplasia that is mainly composed of fibroblastlike synoviocytes (FLSs) combined with a massive infiltration of lymphocytes and macrophages [3,4]. Increased proliferation and insufficient apoptosis might contribute to the expansion of RA FLSs, and several reports suggest inducing apoptosis of RA FLSs as a therapeutic approach [3,4]
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