Abstract
We introduce Synoviolin as a novel pathogenic factor in rheumatoid arthritis (RA). Experimental studies indicate that this endoplasmic reticulum (ER)-resident E3 ubiquitin ligase has important functions in the ER-associated degradation (ERAD) system, an essential system for ER homeostasis. Overexpression of Synoviolin in mice causes arthropathy with synovial hyperplasia, whereas heterozygous knockdown results in increased apoptosis of synovial cells and resistance to collagen-induced arthritis in mice. On the basis of these experimental data, we propose that excess elimination of unfolded proteins (that is, 'hyper-ERAD') by overexpression of Synoviolin triggers synovial cell overgrowth and hence a worsening of RA. Further analysis of the hyper-ERAD system may permit the complex pathomechanisms of RA to be uncovered.
Highlights
There is a general agreement that synovial cells have a crucial function in rheumatoid arthritis (RA) by forming a mass of synovial tissue, which promotes the production of matrixdegrading proteases and osteoclast activation that lead to joint destruction [1,2,3,4,5,6]
We examined the effect of tunicamycin on rheumatoid synovial cells (RSC) treated with small interfering RNA (siRNA) to test whether the downregulation of Synoviolin increases their susceptibility to apoptosis caused by disruption of endoplasmic reticulum (ER) function
We propose a novel hypothesis for RA pathogenesis: ‘hyper-ER-associated degradation (ERAD)’, which may alter the characteristics of synovial cells in RA
Summary
There is a general agreement that synovial cells have a crucial function in rheumatoid arthritis (RA) by forming a mass of synovial tissue, which promotes the production of matrixdegrading proteases and osteoclast activation that lead to joint destruction [1,2,3,4,5,6]. There seems to be sufficient experimental evidence for the following consequences of a hyper-ERAD status: first, enhanced protein production and cell overgrowth; second, maintenance of ER function of synovial cells despite ER stress in the milieu of inflamed joints; and third, prevention of apoptosis induced by ER stress. These processes could worsen the pathological process of RA
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