Comprehensive multi-omics approach reveals potential therapeutic targets and agents for osteoarthritis.

Abstract

Background: The mechanisms underlying osteoarthritis (OA) remain unclear, and effective treatments are lacking. This study aims to identify OA-related genes and explore their potential in drug repositioning for OA treatment.

Methods: Transcriptome-wide association studies (TWAS) were performed using genome-wide association studies summary data and expression quantitative trait loci data from the Genotype-Tissue Expression project. Differentially expressed genes between OA patients and healthy controls were identified using four datasets from the Gene Expression Omnibus database. Gene ontology and pathway enrichment analyses identified potential hub genes associated with OA. A network-based drug repositioning approach was applied to discover potential therapeutic drugs for OA.

Results: Through TWAS and mRNA expression profiling, 7 and 167 OA-related genes were identified, respectively. From these, 128 OA-related genes were selected based on common biological processes. Using the maximal clique centrality algorithm, 10 core-related genes (JUN, VEGFA, FN1, CD44, PTGS2, STAT1, MAP 2K7, GRB2, EP300, and PXN) were identified for network-based drug repositioning. Consequently, 24 drugs were identified based on 128 OA-related genes and 23 drugs based on 10 core OA-related genes. Some identified drugs, such as dexamethasone, menadione, and hyaluronic acid, have been previously reported for OA and/or rheumatoid arthritis treatment. Network analysis also indicated that spironolactone, lovastatin, and atorvastatin may have potential in OA treatment.

Conclusion: This study identified potential OA-related genes and explored their roles in drug repositioning, suggesting the repurposing of existing drugs and the development of new therapeutic options for OA patients. Key message What is already known on this topic The exact pathogenesis of osteoarthritis (OA) remains unclear, and currently, there are no approved drugs that can prevent, halt, or inhibit the progression of OA. What this study adds We identified 128 OA-related genes and 10 core-related genes based on common biological processes revealed by TWAS and mRNA expression profiling. Using these genes, we discovered potential drugs for OA through the Network-based drug repositioning method. How this study might affect research, practice, or policy This study provides recommendations for repositioning existing drugs and developing new treatment options for patients with OA.