Regional analysis of p53 mutations in rheumatoid arthritis synovium

Yamanishi, Yuji; Boyle, David L.; Rosengren, Sanna; Green, Douglas R.; Zvaifler, Nathan J.; Firestein, Gary S.

doi:10.1073/pnas.152333199

Cited by 214Rheumatoid Arthritis Research and TherapiesCancer-related Molecular PathwaysMusculoskeletal synovial abnormalities and treatments

Regional analysis of p53 mutations in rheumatoid arthritis synovium

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Yamanishi, Yuji, Boyle, David L., Rosengren, Sanna, Green, Douglas R., Zvaifler, Nathan J., Firestein, Gary S.·2002·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.152333199PMC PMC126618

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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 the p53 gene can occur because of genotoxic stress in many tissues, including the skin, colon, and synovium. Although somatic mutations in the p53 gene have been demonstrated in rheumatoid arthritis (RA) synovial tissue and synoviocytes, no information is available on the location or extent of p53 mutations. Using microdissected RA synovial tissue sections, we observed abundant p53 transition mutations, which are characteristic DNA damage caused by oxidative stress. p53 mutations, as well as p53 mRNA expression, were located mainly in the synovial intimal lining rather than the sublining ( P < 0.01). Clusters of p53 mutant 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 of p53 mutations contained significantly greater amounts of IL-6 mRNA compared with the low mutation samples ( P < 0.02). The microdissection findings suggest that p53 mutations 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 containing p53 mutations can potentially affect neighboring cells and enhance inflammation through the elaboration of proinflammatory cytokines.

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p53 mutations are seen at frequencies similar to those in tumours in chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.
“Indeed, p53 mutations are seen at frequencies similar to those in tumours in chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease31.”
From Inflammation and cancer (2002) · cites this paper as [31]

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Authors: Yamanishi, Y., Boyle, D. L., Rosengren, S., Green, D. R., Zvaifler, N. J., & Firestein, G. S.
Affiliations: La Jolla Institute for Immunology (US)
ORCID: Boyle, David L.
Rosengren, Sanna
Green, Douglas R.
Firestein, Gary S.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2002-07-15
Volume: 99
Issue: 15
Pages: 10025-10030
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.152333199
PMC: PMC126618
OpenAlex: W2049970248
Cited by: 214
References: 49
Citations by year: 2026: 2 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 15 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 7 · 2016: 12 · 2015: 9 · 2014: 5 · 2013: 15 · 2012: 8
FWCI: 9.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p50ar044850-05)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-44850, AR45347, R01AR045347)
Topics: Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Health Sciences › Medicine › Rheumatology › Musculoskeletal synovial abnormalities and treatments
Keywords: TP53 mutation, rheumatoid arthritis, synovium, synoviocytes, oxidative stress, transition mutations, synovial intima, oligoclonal expansion, IL-6 expression, tumor suppressor, inflammation, microdissection, genotoxic stress
MeSH terms: Arthritis, Rheumatoid, Base Sequence, Humans, Mutation, RNA, Messenger, Synovial Membrane, Interleukin-5, Polymerase Chain Reaction, Genes, p53, DNA Primers, Arthroplasty, Replacement

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Regional analysis of p53 mutations in rheumatoid arthritis synovium

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