Abstract
Surgical synovectomy to remove the inflammatory synovium can temporarily ameliorate rheumatoid inflammation and delay the progress of joint destruction. An efficient medically induced programmed cell death (apoptosis) in the rheumatoid synovium might play a role similar to synovectomy but without surgical tissue damage. Gene transfer of Fas ligand (FasL) has increased the frequency of apoptotic cells in mouse and rabbit arthritic synovium. In this study, we investigated whether repeated FasL gene transfer could remove human inflammatory synovial tissue in situ and function as a molecular synovectomy. Briefly, specimens of human synovium from joint replacement surgeries and synovectomies of rheumatoid arthritis (RA) patients were grafted subcutaneously into male C.B-17 severe combined immunodeficiency (SCID) mice. Injections of a recombinant FasL adenovirus (Ad-FasL) into the grafted synovial tissue at the dosage of 1011 particles per mouse were performed every two weeks. Three days after the fifth virus injection, the mice were euthanized by CO2 inhalation and the human synovial tissues were collected, weighed and further examined. Compared to the control adenovirus-LacZ (Ad-LacZ) and phosphate buffered saline (PBS) injected RA synovium, the Ad-FasL injected RA synovium was dramatically reduced in size and weight (P < 0.005). The number of both synoviocytes & mononuclear cells was significantly reduced. Interestingly, an approximate 15-fold increased frequency of apoptotic cells was observed in RA synovium three days after Ad-FasL injection, compared with control tissues. In summary, our in vivo investigation of gene transfer to human synovium in SCID mice suggests that repeated intra-articular gene transfer of an apoptosis inducer, such as FasL, may function as a 'gene scalpel' for molecular synovectomy to arrest inflammatory synovium at an early stage of RA.
Highlights
Rheumatoid arthritis (RA) is a potentially very disabling disease that is characterized by chronic synovitis, a hyperplasic synovial membrane, and cartilage and bone destruction
Rheumatoid arthritis synovial tissues Synovium and cartilage were obtained from rheumatoid arthritis (RA) patients who were diagnosed according to the 1987 revised criteria of the American College of Rheumatology [23] and who underwent joint replacement surgeries and synovectomies
The results show that the adenovirus vector mediates high dose dependent transgene expression in human synovium (Fig. 1a–d) but not in cartilage (Fig. 1e,f) in vivo three days after virus injection
Summary
Rheumatoid arthritis (RA) is a potentially very disabling disease that is characterized by chronic synovitis, a hyperplasic synovial membrane, and 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 [1,2,3]. 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 [5,6,7] 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 cmyc, c-fos, c-ras, c-jun, and bcl-2 in RA synoviocytes, may lead to inadequate apoptosis and tumor-like proliferation of rheumatoid synoviocytes [8,9,10,11]. 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
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