Mechanisms and clinical relevance of TRAIL‐triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis

Abstract

Objective. Results of studies in mice suggest a protective role for TRAIL in arthritis. The aim of this study was to investigate the role of TRAIL in patients with rheumatoid arthritis (RA).Methods. In the present study, we compared RA fibroblast-like synoviocytes (FLS) that were resistant or sensitive to TRAIL-induced apoptosis and the expression of TRAIL receptors in these cells, and also investigated the clinical features of the patients from whom the FLS were derived. Furthermore, we evaluated the levels of TRAIL and its soluble decoy receptor osteoprotegerin (OPG) in patients with RA, patients with osteoarthritis (OA), and patients with spondylarthritis (SpA).Results. Sensitivity to TRAIL-induced apoptosis varied in FLS from different patients, and the severity of disease in patients with RA was inversely correlated with the susceptibility of their FLS to TRAIL-induced apoptosis. TRAIL-sensitive cells expressed significantly lower levels of TRAILR-1, and silencing of TRAILR-1 increased TRAIL-induced apoptosis in RA FLS. TRAIL levels were elevated in the arthritic joints of patients with established RA, and TRAIL levels in the synovial fluid of these patients were elevated compared with levels in the synovial fluid of patients with OA or SpA. At baseline, a low OPG-to-TRAIL ratio in the sera of patients with early RA was associated with a better evolution of disease activity, but high serum levels of TRAIL at followup were associated with joint damage.Conclusion. These findings suggest that TRAIL has a dual role in RA, and that the resistance of RA FLS to TRAIL-induced apoptosis is associated with a disease-promoting activity of TRAIL in RA.

Soluble TRAIL in normal pregnancy and acute pyelonephritis: a potential explanation for the susceptibility of pregnant women to microbial products and infection

“…sTRAIL is detectable in the serum/plasma of healthy individuals [82–84], and is increased in patients with autoimmune diseases (such as systemic sclerosis, systemic lupus erythematosus (SLE), rheumatoid arthritis) [82,85,86] and viral infection such as human immunodeficiency virus (HIV) [87]. In contrast, serum/plasma concentrations of sTRAIL are decreased in patients with ischemic heart disease [88,89].…”

Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors

“…47 Anomalies in pathways that promote invasiveness and cytokine secretion also favour survival of RA FLS by increasing expression of antiapoptotic molecules, such as apoptosis regulator Bcl-2 (which is over expressed in synovial samples from patients with RA 12 ), and by decreasing or altering the response to ligation of apoptosis-regulating receptors, such as TNF receptor superfamily (TNFRSF) member 6 (also known as CD95 and FAS) 13,48 and TNFRSF10A (also known as TRAIL receptor 1). 49 Reduced apoptosis can, in part, be secondary to increased expression and engagement of integrins on FLS in the RA synovium. 47 Intrinsic deficiencies in apoptosis-specific pathways are also reportedly prominent in RA FLS, especially abnormalities in the p53 pathway.…”

Adenovirus-mediated osteoprotegerin ameliorates cartilage destruction by inhibiting proteoglycan loss and chondrocyte apoptosis in rats with collagen-induced arthritis

“…TRAIL, another receptor for OPG, has been found to promote the apoptosis of chondrocytes in vitro (Pettersen et al 2002). According to research by Audo et al (2011), TRAIL only plays a protective role in the early phase of RA (possibly the first 6 months) and has a deleterious role later on. A possible explanation might lie in its pro-apoptosis effects on chondrocytes.…”