Background/Purpose: Rheumatoid arthritis (RA) is a common and chronic autoimmune disease. Arthritis severity and joint damage predict clinical outcome and the risk for disability in RA. Yet, little is known about disease severity and joint damage regulatory genes. We have previously identified a new nuclear receptor (NR) expression signature in synovial tissues that correlates with arthritis protection and development of mild and non-erosive disease. NR1D1 (Rev-erba) was the NR with the most significant difference in expression in synovial tissues, with an 8.75-fold increase in the protected rats, suggesting that increased levels and activity of NRs have a suppressive effect on disease severity and joint damage. We hypothesized that NR1D1 mediates arthritis protection at least in part via inhibition of the invasiveness of fibroblast-like synoviocytes (FLS) derived from RA patients and arthritic rats, an in vitro phenotype known to correlate with histologic and radiographic joint damage.

Methods: FLS were obtained from DA rats and patients with RA and used after the third passage (>95% FLS purity). Cells were treated with the NR1D1 agonist GSK4112 and studied in an in vitro invasion assay through Matrigel over 24 hours. qPCR was used to quantify the expression of MMPs. Confocal and immunofluorescence microscopy were used to characterize cell and actin cytoskeleton morphologic changes.

Results: Treatment of FLS from arthritic DA rats and from RA patients with the NR1D1 agonist GSK4112 reduced their invasiveness by 70% and 60%, respectively (p<0.002), compared with vehicle. GSK4112 treatment reduced numbers of thick actin filaments, numbers of elongated cells, and the polarized formation of lamellipodia, all actin cytoskeleton and FLS morphologic changes required for invasion. GSK4112 did not significantly affect the IL-1β-induced expression of MMP-1, MMP-2 and MMP-3 in FLS.

Conclusion: We have identified an association between increased synovial expression of NR1D1 and arthritis protection, and a new role for this gene in the regulation of FLS invasion. NR1D1 interferes actin cytoskeletal changes required for cell motility and invasion and could become a useful target for therapies aimed at preserving joint architecture and function.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nr1d1-is-a-new-suppressor-of-rheumatoid-arthritis-fibroblast-like-synoviocyte-invasion/