ER Stress: A Therapeutic Target in Rheumatoid Arthritis?

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 39; no. 7; pp. 610 - 623
• Main Authors: Rahmati, Marveh, Moosavi, Mohammad Amin, McDermott, Michael F.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2018
• Subjects: endoplasmic reticulum; ER stress; ER-associated degradation; rheumatoid arthritis; unfolded protein response; ER stress; unfolded protein response; rheumatoid arthritis; ER-associated degradation; endoplasmic reticulum
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2018.03.010

Diverse physiological and pathological conditions that impact on protein folding of the endoplasmic reticulum (ER) cause ER stress. The unfolded protein response (UPR) and the ER-associated degradation (ERAD) pathway are activated to cope with ER stress. In rheumatoid arthritis (RA), inflammation and ER stress work in parallel by driving inflammatory cells to release cytokines that induce chronic ER stress pathways. This chronic ER stress may contribute to the pathogenesis of RA through synoviocyte proliferation and proinflammatory cytokine production. Therefore, ER stress pathways and their constituent elements are attractive targets for RA drug development. In this review, we integrate current knowledge of the contribution of ER stress to the overall pathogenesis of RA, and suggest some therapeutic implications of these discoveries. ER stress and the subsequent UPR play complex, but complementary, roles in the pathogenesis of RA. Inflammatory cytokines, autoantibodies, hypoxia, and low glucose levels, which are among the essential pathological hallmarks of RA, may act in concert as ER stressors in the synovium. Both conventional and unconventional UPR signaling pathways are involved in proinflammatory cytokine production and the development of the apoptosis-resistant phenotype of synovial cells in RA. GRP78/BiP plays a Janus-like role in the inflammatory milieu and pathogenesis of RA, and both its administration and inhibition have potential therapeutic benefits in the management of patients with RA. Targeting the IRE1 branch of the UPR as well as synoviolin, an ER-resident E3 ubiquitin ligase, may prevent some of the pathological features of RA and has significant therapeutic potential in RA.