In RA synovial tissue a regulation of fibroblast-like synoviocyte (FLS) proliferation and cytokine and matrix metalloproteinase (MMP) expression is vital for tissue homeostasis, but the mechanism(s) that coordinately balances these processes remains largely unknown. During the pathogenesis of rheumatoid arthritis (RA), FLS cell number markedly increase, display a transformed phenotype, and invade and destroy adjacent cartilage. In contrast, osteoarthritis (OA) fibroblasts do not hyperproliferate in vivo and are not responsible for articular cartilage degradation. However, to date only one investigation has focused on the regulation of cell cycle regulatory factors in RA. Mutations in the tumor suppressor protein, p53, which regulates cell growth have also been reported, supporting the notion of a potential dysfunctional cell cycle in RA-FLSs. Furthermore, inhibition of proliferation suppressed FLS cytokine and MMP production, suggesting that inflammatory mediators and cell cycle activity may be linked. Preliminary data demonstrate that the p53 inducible cyclin dependent kinase inhibitor, p2l, a negative regulator of cell cycle activity, is downregulated in RA compared to OA. In addition, FLSs in normal rat ankles are p21-positive, which is decreased following the induction of adjuvant-induced arthritis. Collectively, these data suggest that inhibition of proliferation downregulates the constitutive expression of inflammatory molecules mediated by p21. p2l restoration will inhibit FLS proliferation and ameliorate adjuvant- induced arthritis in rats. Thus, in this proposal we will demonstrate that adenoviral mediated delivery of the p2l gene in FLS will induce Go/Gl cell cycle arrest and prevent cytokine/MMP production in vitro and in vivo. This approach could lead to the development of a new therapeutic approach strategy for gene therapy in patients with RA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Comprehensive Center (P60)
Project #
5P60AR030692-17
Application #
6310707
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1983-12-01
Project End
2001-11-30
Budget Start
Budget End
Support Year
17
Fiscal Year
2000
Total Cost
$174,159
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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