Regional analysis ofp53mutations in rheumatoid arthritis synovium

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Abstract
The p53 tumor suppressor protein plays a central role in cell cycle regulation, DNA repair, and apoptosis. Recent studies indicate that DNA damage and somatic mutations in thep53gene can occur because of genotoxic stress in many tissues, including the skin, colon, and synovium. Although somatic mutations in thep53gene have been demonstrated in rheumatoid arthritis (RA) synovial tissue and synoviocytes, no information is available on the location or extent ofp53mutations. Using microdissected RA synovial tissue sections, we observed abundantp53transition mutations, which are characteristic DNA damage caused by oxidative stress.p53mutations, as well asp53mRNA expression, were located mainly in the synovial intimal lining rather than the sublining (P< 0.01). Clusters ofp53mutant subclones were observed in some microdissected regions, suggesting oligoclonal expansion. Because IL-6 gene expression is regulated by wild-type p53, IL-6 mRNA expression in microdissected tissues was quantified by using real-time PCR. The regions with high rates ofp53mutations contained significantly greater amounts of IL-6 mRNA compared with the low mutation samples (P< 0.02). The microdissection findings suggest thatp53mutations are induced in RA synovial tissues by inflammatory oxidative stress. This process, as in sun-exposed skin and inflamed colonic epithelium, provides some of the mutant clones with a selective growth advantage. A relatively low percentage of cells containingp53mutations can potentially affect neighboring cells and enhance inflammation through the elaboration of proinflammatory cytokines.