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DNA mismatch repair enzyme expression in synovial tissue
E Simelyte1, D L Boyle, G S Firestein
1Division of Rheumatology, Allergy, and Immunology, School of Medicine, University of California at San Diego, La Jolla 92093-0656, USA.
Annals of the Rheumatic Diseases
|November 18, 2004
Summary
DNA mismatch repair (MMR) enzyme expression is elevated in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium, particularly in the intimal lining. However, this increase doesn't prevent DNA damage accumulation in the genotoxic environment of RA.
Area of Science:
- Rheumatology and Molecular Biology
- Genetics and DNA Repair Mechanisms
Background:
- Oxidative stress in rheumatoid arthritis (RA) synovial tissue can lead to DNA damage.
- This damage can suppress the DNA mismatch repair (MMR) system, involving enzyme complexes hMutSalpha (hMSH2/hMSH6) and hMutSbeta (hMSH2/hMSH3).
Purpose of the Study:
- To investigate the expression and distribution of MMR enzymes in synovial tissues.
- Comparison between patients with arthritis (RA, OA) and normal subjects.
Main Methods:
- Immunohistochemistry was used to analyze synovial tissues from RA, OA, and normal subjects.
- Monoclonal antibodies against hMSH2, hMSH3, and hMSH6 were employed.
- Computer-assisted digital image analysis quantified MMR protein expression.
Main Results:
- MMR enzymes (hMSH2, hMSH3, hMSH6) were detected in most synovial tissues, with higher levels in the intimal lining.
- RA and OA tissues showed significantly higher sublining expression of these enzymes compared to normal synovium.
- MMR enzymes were primarily expressed by CD68(+) and CD68(-) cells in the intimal lining.
Conclusions:
- DNA MMR enzyme expression is highest in the synovial intimal lining, a site of maximal oxidative stress in RA.
- Despite increased MMR enzyme expression in RA, it is insufficient to counteract the genotoxic environment, leading to DNA damage accumulation.