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Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium
G S Firestein1, F Echeverri, M Yeo
1Division of Rheumatology, University of California, San Diego, CA 92093-0656, USA.
Abstract:
The factors that regulate the perpetuation and invasiveness of rheumatoid synovitis have been the subject of considerable inquiry, and the possibility that nonimmunologic defects can contribute to the disease has not been rigorously addressed. Using a mismatch detection system, we report that synovial tissue from the joints of severe chronic rheumatoid arthritis patients contain mutant p53 transcripts, which were not found in skin samples from the same patients or in joints of patients with osteoarthritis. Mutant p53 transcripts also were identified in synoviocytes cultured from rheumatoid joints. The predicted amino acid substitutions in p53 were identical or similar to those commonly observed in a variety of tumors and might influence growth and survival of rheumatoid synoviocytes. Thus, mutations in p53 and subsequent selection of the mutant cells may occur in the joints of patients as a consequence of inflammation and contribute to the pathogenesis of the disease.
Insights
Rheumatoid arthritis patients
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Background:
- Rheumatoid synovitis perpetuation and invasiveness are poorly understood.
- Nonimmunologic defects' role in rheumatoid arthritis (RA) remains under-explored.
Purpose of the Study:
- To investigate the presence and significance of mutant p53 transcripts in rheumatoid arthritis synovial tissue.
- To explore the potential contribution of p53 mutations to RA pathogenesis.
Main Methods:
- Utilized a mismatch detection system to analyze synovial tissue and cultured synoviocytes from RA patients.
- Compared findings with skin samples from RA patients and synovial tissue from osteoarthritis patients.
Main Results:
- Mutant p53 transcripts were detected in synovial tissue and cultured synoviocytes from severe chronic rheumatoid arthritis patients.
- These mutant p53 transcripts were absent in control skin samples and osteoarthritis joints.
- Predicted p53 amino acid substitutions resembled those found in various tumors.
Conclusions:
- Mutations in p53 may occur in the joints of RA patients due to inflammation.
- Selection of these mutant cells could contribute to the pathogenesis of rheumatoid arthritis.
- This suggests a potential nonimmunologic defect contributing to RA.