# RA-risk synovium exhibits DNA damage coupled with impaired DNA repair in fibroblasts

## TL;DR

This study shows that DNA damage and poor repair in synovial tissue appear early in rheumatoid arthritis, suggesting a new target for early treatment.

## Contribution

The study identifies early DNA damage and impaired repair in RA-risk synovium and shows that senolytic drugs can partially restore repair.

## Key findings

- DNA damage is present in synovial fibroblasts and T cells during the preclinical RA-risk phase.
- RA-risk and RA fibroblasts show increased DNA damage and reduced repair capacity compared to controls.
- Senolytic drugs partially restore DNA repair in RA-risk and RA synovial fibroblasts in vitro.

## Abstract

Understanding the molecular changes in the preclinical synovium is crucial for identifying factors that drive arthritis development. Persistent DNA damage in tissues is known to drive a senescent microenvironment, genomic instability and ultimately chronic inflammation. Here, we determined cellular DNA damage and repair capacity within synovial tissue from rheumatoid arthritis (RA) patients and individuals at risk of developing RA.

We investigated the presence of senescence-associated DNA damage in synovial biopsies and synovial fibroblasts obtained during different phases of RA. Histone 2A is phosphorylated (γH2AX) at the site of a double-stranded DNA break where DNA repair proteins are recruited and is therefore a proxy measurement for DNA damage. In this study, we employed immunofluorescence staining for γH2AX on synovial tissue sections and cultured synovial fibroblasts alongside quantitative PCR for a panel of DNA repair proteins.

We demonstrated the presence of DNA damage in both synovial fibroblasts and T cells during the preclinical, RA-risk phase of disease. Furthermore, cultured synovial fibroblasts from RA-risk individuals and RA patients exhibited increased DNA damage and a reduced capacity for DNA repair compared with synovial fibroblasts from control individuals. Finally, treatment with senolytic drugs partially restored the DNA damage repair capacity in RA and RA-risk synovial fibroblasts in vitro.

Our findings reveal persistent DNA damage in the preclinical phase of RA in both synovial tissue and fibroblasts, suggesting a role in disease progression. The partial restoration of DNA repair in synovial fibroblasts by senolytic treatment highlights its potential therapeutic target for preventative therapy in RA-risk individuals.