Abstract
Fibroblast-like synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA), yet little is known about its regulation. In this study we aimed to determine the role of the nuclear receptor liver X receptor (LXR) in FLS invasion. FLS were isolated from synovial tissues obtained from RA patients and from DA rats with pristane-induced arthritis. Invasion was tested on Matrigel-coated chambers in the presence of the LXR agonist T0901317, or control vehicle. FLS were cultured in the presence or absence of T0901317, and supernatants were used to quantify matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, interleukin-6 (IL-6), tumor necrosis factor-α and C-X-C motif chemokine ligand 10 (CXCL10). Nuclear factor-κB (NF-κB) (p65) and Akt activation, actin cytoskeleton, cell morphology and lamellipodia formation were also determined. The LXR agonist T0901317 significantly reduced DA FLS invasion by 99% (P ≤ 0.001), and RA FLS invasion by 96% (P ≤ 0.001), compared with control. T0901317-induced suppression of invasion was associated with reduced production of activated MMP-2, IL-6 and CXCL10 by RA FLS, and with reduction of actin filament reorganization and reduced polarized formation of lamellipodia. T0901317 also prevented both IL-1β-induced and IL-6-induced FLS invasion. NF-κB (p65) and Akt activation were not significantly affected by T0901317. This is the first description of a role for LXR in the regulation of FLS invasion and in processes and pathways implicated both in invasion as well as in inflammatory responses. These findings provide a new rationale for considering LXR agonists as therapeutic agents aimed at reducing both inflammation and FLS-mediated invasion and destruction in RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects 0.5–1% of the population and is associated with increased risk for joint deformities, disability, and reduced longevity [1,2]
We have previously shown that liver X receptor α (LXRα) and its targets are expressed in reduced levels in synovial tissues and in fibroblast-like synoviocyte (FLS) from DA rats compared with arthritis-resistant rats [10]
LXRβ is expressed by DA synovial tissues and FLS, but levels were similar to those in arthritis-resistant rats, and less likely to account for the differences in disease severity
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects 0.5–1% of the population and is associated with increased risk for joint deformities, disability, and reduced longevity [1,2]. The fibroblast-like synoviocyte (FLS) has a central role in the formation of the RA synovial pannus and in joint destruction [3,4]. The in vitro invasive properties of FLS from patients with RA and from rats with pristane-induced arthritis (PIA) through collagen-rich Matrigel have been shown to correlate with radiographic erosive changes and with histological joint damage, respectively [5,6]. Erosive changes and joint damage correlate with worse disease outcome, including increased risk for disability and for the development of deformities [7,8,9]. Understanding of the processes and genes regulating FLS invasion has the potential to generate new targets for therapies aimed at reducing articular damage as well as improving disease outcome
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