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Hyper-ERAD: a novel pathomechanism for rheumatoid arthritis

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Rheumatoid arthritis (RA) is a joint-affecting disease and is characterized with overgrowth of articular synovial cells, so-called 'pannus'. To understand the pathomechanism of RA, we attempted to characterize the rheumatoid synovial cell and found a novel protein, 'Synoviolin (synovial cell + protein)'. Structural analysis indicated that Synoviolin is an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase, which is important for 'ER-associated degradation (ERAD)'. Its overexpression causes arthropathy, resembling RA in mice. Moreover, the heterozygote of Synoviolin (+/-) is remarkably resistant to collagen-induced arthritis. These 'gain of function' and 'loss of function' analyses clearly indicate the important role of Synoviolin in arthropathy.

Therefore, we present a new pathogenic mechanism for RA that is related with ERAD, an essential system for ER homeostasis by eliminating unfolded proteins from the organelle. Recent studies have shown that the accumulation of unfolded proteins mediated by impaired ERAD system results in ER stress-induced apoptosis of cells and causes various degenerative human diseases. Besides, the ERAD system is tightly linked with cell growth, apoptosis and differentiation. This evidence led us to a new hypothesis that 'hyper function of ERAD system' may cause synovial cell overgrowth through its anti-apoptotic effect in RA. Thus, we propose that inhibition of Synoviolin is one of the promising strategies for RA treatment by targeting synovial cells.

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Nakajima, T., Yagishita, N., Yamasaki, S. et al. Hyper-ERAD: a novel pathomechanism for rheumatoid arthritis. Arthritis Res Ther 6, 6 (2004) doi:10.1186/ar1340

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Keywords

  • Rheumatoid Arthritis
  • Endoplasmic Reticulum
  • Ubiquitin Ligase
  • Pathogenic Mechanism
  • Arthropathy