Synoviolin and Rheumatoid Arthritis

Abstract

DEVELOPMENT Rheumatoid arthritis (RA) afflicts nearly 1% of the worldwide adult population. Cytokines released from immune cells cause chronic inflammation and stimulate the proliferation of synovial cells that destroy bone and cartilage of joints. But nearly 25% of RA patients do not respond to anti-cytokine therapy. This may be because synovial cell growth is also controlled by an enzyme called synoviolin. Amano et al. detected elevated synoviolin expression in the synovial tissue of RA patients. Mice overexpressing this molecule exhibited spontaneous arthropathy and a progressive synovial cell hyperplasia characteristic of RA patients. Reduced expression of synoviolin in mice correlated with protection from arthritis. This resistance was not due to an impaired cytokine response or reduced inflammatory cell infiltration, but to an increase in synovial cell apoptosis. Knockdown of synoviolin expression in rheumatoid synovial cells by RNA interference suppressed growth responses to cytokines. Synoviolin-null mouse fibroblasts also showed enhanced apoptosis induced by endoplasmic reticulum-related stress, suggesting a possible anti-apoptotic mechanism, and marking synoviolin as a possible drug target to treat RA. Synoviolin is an E3 ubiquitin ligase, but the role of its enzymatic activity in the pathogenesis of RA is not yet known. — LDC Genes Dev . 10.1101/gad.1096603 (2003).