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Gene transfer of p21Cip1 exerts multiple molecular effects in the treatment of arthritis

Forced expression of the cyclin-dependent kinase inhibitor gene p21cip1in the synovial tissues was effective in treating animal models of rheumatoid arthritis (RA). Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p21cip1 on cell-cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To determine why the cell-cycle regulator gene exerted such anti-inflammatory effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21cip1 gene transferred. We have found that p21cip1 gene transfer downregulates the expression of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of RA. These molecules included IL-6, IL-8, type I IL-1 receptor (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3a, cathepsins B and K, and matrix metalloproteinase-1 and matrix metalloproteinase-3. Downregulation of IL-1R1 by p21cip1 resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21cip1 was seen even when IL-1 is absent. This IL-1R1-independent suppression was accompanied by reduced activity of c-Jun N-terminal kinase, which was associated with p21cip1, and by inactivation of NF-κB and AP-1. These multiple regulatory effects should work in concert with the primary effect of inhibiting the cell cycle in ameliorating the arthritis, and suggest a heretofore unexplored relationship between cyclin-dependent kinase inhibitors and inflammatory molecules.

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Kohsaka, H., Nonomura, Y., Nagasaka, K. et al. Gene transfer of p21Cip1 exerts multiple molecular effects in the treatment of arthritis. Arthritis Res Ther 5 (Suppl 3), 134 (2003).

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