Nitric oxide is a mediator of apoptosis in the rheumatoid joint

Objective. To study the role of nitric oxide (NO) derived from the inducible nitric oxide synthase (iNOS) pathway in the induction of apoptosis in the rheumatoid joint. Methods. Joint tissue was obtained from four rheumatoid arthritis (RA) patients, three osteoarthritis patients and two patients with a fractured neck of the femur (NOF#), and apoptotic cells were identified in cryosections using the TUNEL (terminal dUTP nick end labelling) assay. Expression of iNOS was determined using immunohistochemistry. NO synthesis and the effect of NOS inhibitors on apoptosis levels were studied in explant cultures of RA cartilage and synovium. Results. Numbers of apoptotic cells were greatly increased in rheumatoid synovium and articular cartilage compared with NOF# and osteoarthritic synovium. Immunohistochemistry showed co-localization of iNOS staining and apoptosis in the synovial lining layer and articular cartilage. The NOS inhibitor L-NMMA (L-N-G-monomethylarginine) strongly inhibited apoptosis in explant cultures of synovium and cartilage, and this was reversed by the NO donor S-nitroso-acetyl-penicillamine. Conclusion. This study indicates that NO acts as a mediator of apoptosis in RA and suggests that NOS inhibitors reverse this process.