Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that primarily affects joints. In rheumatoid joints there is extensive synovial proliferation with diseased synovium becoming highly aggressive, attaching to the articular cartilage and bone to form what is termed a pannus. The formation of active pannus is central to erosive disease and resulting joint destruction. In this study, we examined the ability to eliminate the hyperplastic synovium by adenoviral-mediated gene transfer of human TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family that is able to induce apoptosis through interaction with receptors containing death domains, DR4 and DR5. Infection of synovial cells derived from RA patients with Ad.TRAIL resulted in significant apoptosis in three out of five lines. Moreover, primary rabbit synovial fibroblasts were also sensitive to Ad.TRAIL-mediated gene transfer. In a rabbit model of arthritis, intra-articular gene transfer of TRAIL induced apoptosis in cells within the synovial lining, reduced leukocytic infiltration and stimulated new matrix synthesis by cartilage. These results demonstrate that TRAIL can affect the viability of the cells populating the activated synovium in arthritic joints and suggest that the delivery of TRAIL to arthritic joints may represent a non-invasive mechanism for inducing pannus regression.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Firestein GS . Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum 1996; 39: 1781–1790.
Qu Z et al. Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organizer region staining. Arthritis Rheum 1994; 37: 212–220.
Muller-Ladner U, Gay RE, Gay S . Activation of synoviocytes. Curr Opin Rheumatol 2000; 12: 186–194.
Ritchlin C . Fibroblast biology. Effector signals released by the synovial fibroblast in arthritis. Arthritis Res 2000; 2: 356–360.
Ritchlin C, Dwyer E, Bucala R, Winchester R . Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole synovial tissue obtained from inflammatory synovitis. Scand J Immunol 1994; 40: 292–298.
Hogan M et al. Differential expression of the small inducible cytokines GRO alpha and GRO beta by synovial fibroblasts in chronic arthritis: possible role in growth regulation. Cytokine 1994; 6: 61–69.
Bucala R, Ritchlin C, Winchester R, Cerami A . Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. J Exp Med 1991; 173: 569–574.
Muller-Ladner U et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol 1996; 149: 1607–1615.
Muller-Ladner U, Kriegsmann J, Gay RE, Gay S . Oncogenes in rheumatoid arthritis. Rheum Dis Clin North Am 1995; 21: 675–690.
Firestein GS, Yeo M, Zvaifler NJ . Apoptosis in rheumatoid arthritis synovium. J Clin Invest 1995; 96: 1631–1638.
Yao Q et al. Adenoviral mediated delivery of FAS ligand to arthritic joints causes extensive apoptosis in the synovial lining. J Gene Med 2000; 2: 210–219.
Yao Q et al. Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. Mol Ther 2001; 3: 901–910.
Wiley SR et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3: 673–682.
Pitti RM et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271: 12 687–12 690.
Pan G et al. The receptor for the cytotoxic ligand TRAIL. Science 1997; 276: 111–113.
Walczak H, Krammer PH . The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res 2000; 256: 58–66.
Lincz LF, Yeh TX, Spencer A . TRAIL-induced eradication of primary tumour cells from multiple myeloma patient bone marrows is not related to TRAIL receptor expression or prior chemotherapy. Leukemia 2001; 15: 1650–1657.
Schneider P et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 1997; 7: 831–836.
Pan G et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997; 277: 815–818.
Walczak H et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 1997; 16: 5386–5397.
Screaton GR et al. TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL. Curr Biol 1997; 7: 693–696.
Emery JG et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273: 14 363–14 367.
Schneider P et al. Characterization of two receptors for TRAIL. FEBS Lett 1997; 416: 329–334.
Pan G et al. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Lett 1998; 424: 41–45.
Marsters SA et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 1997; 7: 1003–1006.
Degli-Esposti MA et al. The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 1997; 7: 813–820.
Zhang XD et al. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 1999; 59: 2747–2753.
Yeh P, Perricaudet M . Advances in adenoviral vectors: from genetic engineering to their biology. FASEB J 1997; 11: 615–623.
Acknowledgements
This work was support in part by contract AR-6-2225 from the National Institute of Arthritis and Musculoskeletal Diseases and by a grant from Valentis Corporation.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yao, Q., Wang, S., Gambotto, A. et al. Intra-articular adenoviral-mediated gene transfer of trail induces apoptosis of arthritic rabbit synovium. Gene Ther 10, 1055–1060 (2003). https://doi.org/10.1038/sj.gt.3301881
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301881
Keywords
This article is cited by
-
TNF-related apoptosis-inducing ligand (TRAIL) in rheumatoid arthritis: what’s new?
Clinical and Experimental Medicine (2014)
-
Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis
Rheumatology International (2012)
-
TRAIL Death Receptor-4, Decoy Receptor-1 and Decoy Receptor-2 Expression on CD8+ T Cells Correlate with the Disease Severity in Patients with Rheumatoid Arthritis
BMC Musculoskeletal Disorders (2010)
-
La terapia genica nella riparazione cartilaginea
Archivio di Ortopedia e Reumatologia (2009)
-
Transgene Persistence and Cell Turnover in the Diarthrodial Joint: Implications for Gene Therapy of Chronic Joint Diseases
Molecular Therapy (2007)