Prevention of Nitric Oxide Production and Cell Deaths by Estrogen in Estrogen Receptor Expressed Rheumatoid Arthritis Fibroblasts

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We performed a series of experiments hypothesizing that pathogenesis of RA is initially caused by generations of ROS from mitochondria and binding with NO results in lipid peroxidation and subsequent apoptosis. In addition we hypothesized that estrogen regulates mitochondrial ROS and NO productions and lipid peroxidation as a potential factors for the inhibition of apoptosis in synovial fibroblasts in RA, and these effects were dependent on the expressions of ERs.This study indicated that (1)in RA, mitochondrial ROS and NO would be key players to cause RA pathogenesis by subsequent increase in lipid peroxidation and apoptosis ; (2)estrogen and the binding to ER plays an important role in protecting cells against cytokine-induced apoptotic cell death by controlling the generations of mitochondrial ROS and NO and lipid peroxidation in synovial fibroblasts ; (3)the differential expression of ER_results in different generations of mitochondrial ROS, NO, lipid peroxidation and subsequent apoptosis. These results support the overall hypothesis that intracellular mitochondrial ROS and NO generations and production of lipid peroxidation products subsequently accelerates apoptotic cell death and they are regulated by binding of estrogen to ER_in synovial fibroblasts.