Comprehensive Bioinformatics Analysis Reveals Associations between the DNA Damage Response and Osteoarthritis.

Abstract

Introduction: DNA damage in chondrocytes has been found to be associated with osteoarthritis (OA) and could be a primary pathological mechanism of the disease. Here, we performed transcriptomic analysis of human chondrocytes using existing RNA-seq datasets to characterize DNA damage repair pathway alterations associated with OA status.

Methods: We collected 9 public RNA-seq datasets of cartilage samples in the Gene Expression Omnibus from 57 OA patients and 35 non-OA controls. We identified differentially expressed genes (DEGs), examined enriched pathways, and predicted regulatory networks of the DNA damage response (DDR) in OA by comparing RNA-seq data from OA and non-OA chondrocytes. Furthermore, we evaluated the potential associations between DDR-related gene signatures and OA status.

Results: We identified 490 upregulated and 350 downregulated DEGs in OA. The upregulated DEGs are significantly enriched in DDR pathways, including the Fanconi anemia, mismatch repair, and base excision repair pathways. A total of 10 significant DDR downstream pathways were enriched and upregulated in OA, including DNA replication, DNA repair, and cell cycle pathways in relation to the DDR. Finally, we identified 9 core genes for DNA damage repair in OA (DDR-OA genes) as potential targets for OA biomarkers. Three of these genes are known to be associated with both DDR processes and OA pathology.

Conclusion: Elevated expression of DDR-related genes and enhanced activity of DDR signaling pathways were observed in conjunction with OA onset and progression. Our computational analysis prioritizes identified DDR-OA genes as high-confidence candidates for further experimental investigation.