Background/Purpose: Endoplasmic reticulum (ER) stress is a cellular signal, which is triggered by the failure to fold newly synthesized ER proteins. ER stress plays an important role in the pathogenesis of some human diseases. Recently it was revealed that the rheumatoid arthritis (RA) causes synovial cell tolerance against ER stress during secretion of inflammatory cytokines. ER stress transducer IRE1 is one of the canonical transducers. The activation of IRE1 was identified in RA. Here, we report that IRE1 is a master regulator of the unfolded protein response in RA synovium. And, we demonstrated that the tolerance for ER stress was reduced by inhibiting IRE1 in RA synovial cells. Furthermore, this is the first report to apply STF-083010, a novel small-molecule inhibitor of IRE1, for treatment of RA synovitis.

Methods: Synovial fibroblasts from the knee joint of RA patient who underwent total knee replacement were prepared by digestion with collagenase. We assessed the ER-related genes in the RA patient’s primary cultured synovial fibroblasts.

To investigate the effectiveness of suppressing the synovitis by IRE1 inhibitor, we prepared antigen induced arthritis (AIA) mice model. To prepare the AIA mouse model, arthritis was induced in knee joints of 8-week-old wild-type mice by intra-articular injection of methylated bovine serum albumin (mBSA; Sigma) in mice preimmunized with mBSA. On day 1, mice were preimmunized by a 100 μL intradermal injection at the base of the tail with an emulsion containing 100 μg of mBSA and an equal volume of Freund’s complete adjuvant (Sigma). On day 10, animals were treated with intra-articular mBSA injected into the left and right knee joints. On day 17, the knee joints were harvested and processed using standard procedures.

Results: Although all ER stress transducers were up-regulated with the time, IRE1 exhibited dynamic up-regulation in response to inflammatory stimulation in RA synovial fibroblast group. To assess the effectiveness of IRE1 inhibitor, STF-083010, we also performed TUNEL staining using RA patient’s synovial fibroblasts. We found that the TUNEL-positive cells were significantly increased especially in the STF-083010-treated group. The synovitis of AIA was significantly suppressed in STF-083010-treated AIA group.

Conclusion: STF-083010 inhibited IRE1 activity through ER stress shown in both in vitro and in vivo assays. Treatment with STF-083010 resulted in a significant reduction in cell viability in primary cultured human RA synovial fibroblasts. Similarly, STF-083010 successfully suppressed synovial activity in AIA mouse models as the result of less tolerated to ER stress. This procedure could be considered ‘the molecular targeted synovectomy’. The application of this novel IRE1 inhibitor supports the hypothesis that IRE1 is a promising target for alternative therapy in RA synovitis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/stf-083010-the-inhibitor-of-er-stress-transducer-ire1-suppresses-rheumatoid-synovitis/