Abstract
Gene therapy that results in apoptosis of synovial fibroblasts
Highlights
A prominent feature of the rheumatoid synovium is the dysregulated hyperplasia of SFs due to a postulated imbalance between growth and apoptosis signals
rheumatoid arthritis synovial fibroblasts (RASFs) were resistant to TNFa-mediated apoptosis; this resistance was lost upon transduction with AdCMVI?B-DN, associated with caspase 3 activation
X-linked inhibitor of apoptosis (XIAP) was shown to be induced in RASFs by tumour necrosis factor (TNF)-a in a dose-dependent manner through an NF-?B dependent mechanism, since it could be blocked by infection of cells with AdCMVI?B-DN
Summary
A prominent feature of the rheumatoid synovium is the dysregulated hyperplasia of SFs due to a postulated imbalance between growth and apoptosis signals. Stimulation of SFs from RA patients with TNF-a results in enzyme secretion, which may contribute to articular destruction. Induction of apoptosis of this fibroblast population may represent a potential therapeutic approach in RA. Stimulation of cells by TNF-a can generate two signals: one initiates apoptosis, whereas the second leads to activation of NF-?B (which in turn produces inhibitors of apoptosis [IAPs] and promotes the production of proinflammatory factors). To induce an apoptotic response in RASFs to TNF-a through adenoviral expression of a truncated stable form of I?Ba and expression of an antisense fragment to XIAP
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