Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Mechanisms and Clinical Relevance of TRAIL-Triggered Responses in Synovial Fibroblasts of Rheumatoid Arthritis Patients.

Audo4,  Rachel, Hamaty5,  Flavia Calmon, Baeten1,  Dominique, Combe2,  Bernard G., Hahne4,  Michael, Morel3,  Jacques

Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
Department of Rheumatology. Teaching Hospital of Lapeyronie, Montpellier, France
Department of Rheumatology. Teaching Hospital of Lapeyronie, Montpellier, France
IGMM, UMR5535, CNRS, Montpellier, Montpellier, France
IGMM, UMR5535, CNRS, Montpellier

Background:

Studies in mice suggest a protective role for the TNF-related apoptosis-inducing ligand (TRAIL) in arthritis. We investigated the role of TRAIL in rheumatoid arthritis (RA) patients. We have shown that exposure to TRAIL induces apoptosis only in a portion of RA Fibroblast-Like Synoviocytes (FLS) and that in the surviving cells, TRAIL induced proliferation. In the present study, we compared FLS resistant and RAFLS-sensible to TRAIL-induced apoptosis including levels of the TRAIL receptors (TRAIL-R) and clinical features of respective patient. Furthermore, we evaluated TRAIL levels in RA patients.

Method:

FLS were extracted from synovial tissue of RA patients (n=30) and analyzed by FACS for expression of TRAIL-receptors. We obtained DAS28 within the 3 months of surgery for 13 patients. TRAIL-responses of FLS were analyzed by FACS for apoptosis and thymidine-incorporation for proliferation. TRAIL receptor activity was assessed by RNA silencing. HIC were performed to evaluate TRAIL level in synovial tissues from RA (n=7) and OA patients (n=4). ELISA was used to determine TRAIL-levels in synovial fluid of osteoarthritis (OA; n=20), spondylarthritis (SpA; n=20) and establish RA patients (n=30). Serum levels of TRAIL and its soluble decoy-receptor osteoprotegerin (OPG) were measured by ELISA in 72 patients fulfilling the ACR criteria (1987) with recent (<2 years) and active (>3 swollen joints) RA that were not treated or had a stable background treatment for at least 1 month (M0). 48 of the RA patients were followed up at 6 months (M6).

Results:

Depending on the patient, we observed variability in RAFLS sensitivity to TRAIL-induced apoptosis. We therefore classified the cultures depending on their sensitivity (<10%; RAFLS-R, n=10 and >at 30%, RAFLS-S, n=11). Disease activity of RA patients inversely correlated with susceptibility of FLS to TRAIL-induced apoptosis (r=-0.688, p=0.0092, n=13). TRAIL-S cells expressed significantly lower levels of TRAIL-R1 (p=0.014) and silencing of TRAIL-R1 increased TRAIL-induced apoptosis in RA FLS (p<0.05; n=7). TRAIL levels were elevated in the arthritic joints of patients with established RA and synovial fluids displayed elevated TRAIL levels compare to those of OA and SpA patients (p<0.0001 and p=0,002 respectively). In early RA, patients in remission at M6 (DAS28<2.6) (n=14) had a lower ratio OPG/ TRAIL at baseline than patients without remission (n=34) (0.54 ± 0.25 and 0.94 ± 0.71 respectively, p=0.028), but high serum levels of TRAIL at M6 were associated with joint damages (p=0.0063).

Conclusion:

Surprisingly, TRAIL-R1 seems to be a survival factor protecting RAFLS against TRAIL-induced apoptosis. Furthermore, we found a negative correlation between TRAIL sensitivity RAFLS in vitro and RA activity, suggesting that RAFLS develop resistance to TRAIL-induced apoptosis to escape TRAIL protective role. Indeed, in early RA patient, a low OPG/TRAIL ratio at baseline was associated with remission at 6 months but persistent TRAIL serum levels are associated with joint damage. These findings suggest a dual role for TRAIL in RA and resistance of RA FLS to TRAIL-induced apoptosis is associated with a disease promoting activity of TRAIL in RA.

To cite this abstract, please use the following information:
Audo, Rachel, Hamaty, Flavia Calmon, Baeten, Dominique, Combe, Bernard G., Hahne, Michael, Morel, Jacques; Mechanisms and Clinical Relevance of TRAIL-Triggered Responses in Synovial Fibroblasts of Rheumatoid Arthritis Patients. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1527
DOI: 10.1002/art.29293

Abstract Supplement

Meeting Menu

2010 ACR/ARHP