Intra-articular injection of recombinant TRAIL induces synovial apoptosis and reduces inflammation in a rabbit knee model of arthritis |
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Authors: | Qingping?Yao Dai-Wu?Seol Zhibao?Mi Email author" target="_blank">Paul?D?RobbinsEmail author |
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Institution: | (1) Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA;(2) Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA |
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Abstract: | We demonstrated previously that local, intra-articular injection of an adenoviral vector expressing human tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) in a rabbit knee model of inflammatory arthritis stimulated synovial apoptosis and reduced
inflammation. To examine whether intra-articular injection of recombinant chimeric human TRAIL protein (rTRAIL) also induces
apoptosis of proliferating rabbit synovium and reduces inflammation, we used an experimental rabbit arthritis model of rheumatoid
arthritis, induced by intra-articular introduction of allogeneic fibroblasts genetically engineered to secrete human IL-1β.
Analysis of synovium isolated from the rabbits treated with intra-articular injection of rTRAIL, relative to saline control,
showed areas of extensive acellular debris and large fibrous regions devoid of intact cells, similar to adenoviral mediated
TRAIL gene transfer. Extensive apoptosis of the synovial lining was demonstrated using TUNEL analysis of the sections, corresponding
to the microscopic findings in hematoxylin and eosin staining. In addition, leukocyte infiltration into the synovial fluid
of the inflamed knee joints following rTRAIL treatment was reduced more than 50% compared with the saline control. Analysis
of the glycosaminoglycan synthetic rate by cultured cartilage using radiolabeled sulfur and cartilage histology demonstrated
that rTRAIL did not adversely affect cartilage metabolism and structure. Analysis of serum alanine aminotransferase showed
that intra-articular injection of rTRAIL did not have adverse effects on hepatic function. These results demonstrate that
intra-articular injection of rTRAIL could be therapeutic for treating pathologies associated with rheumatoid arthritis. |
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