Elimination of rheumatoid synovium in situ using a Fas ligand 'gene scalpel'

Rheumatoid arthritis (RA) is a potentially very disabling disease that is characterized by chronic synovitis, a hyperplasic synovial membrane, and finally cartilage and bone destruction. Overgrowth of fibroblast-like synoviocytes as well as their secretion of an impressive array of cytokines/chemokines, adhesion molecules and proteases play important roles in the pathogenesis of rheumatoid joint destruction [1-3]. Surgical synovectomy to remove the inflammatory synovium can temporarily ameliorate rheumatoid inflammation and delay the progress of joint destruction [4]. An efficient medically induced programmed cell death (apoptosis) in the inflammatory synovium [5-7] might play a role similar to surgical synovectomy.Hyperplasia of the rheumatoid synovium may result from the imbalance between cell proliferation and apoptosis. Mutations in tumor suppressor genes such as p53, and elevated expression of proto-oncogenes and apoptosis inhibitors, such as c-myc, c-fos, c-ras, c-jun, and bcl-2 in RA synoviocytes, may lead to inadequate apoptosis and tumor-like proliferation of rheumatoid synoviocytes [8-11]. Thus, the induction of apoptosis by gene transfer of an apoptosis inducer or growth modulator in a sense or anti-sense orientation may function as a 'gene scalpel' for decreasing or eliminating the hyperplasia of the synovial membrane.Fas, a membrane-bound death molecule, is highly expressed in RA synovial lining and sub-lining cells compared to osteoarthritis and normal synovial tissues [11]. Between 30% and 90% of cells in RA synovium are positive for Fas antigen, but Fas ligand (FasL) mRNA has been detected only in mononuclear cells in RA synovium [10]. The upregulation of Fas-mediated apoptosis in inflammatory synovium has been established by intra-articular administration of adenovirus mediated FasL gene [5,12], anti-Fas monoclonal antibodies [13-15], and FasL transfectants [16]. Current reports indicate that a medically induced upregulation of the Fas-mediated apop