The current study aimed to identify gene signatures during rheumatoid arthritis (RA) and osteoarthritis (OA), and used these to elucidate the underlying modular mechanisms. Using the Gene Expression Omnibus database, the present study obtained the GSE7669 mRNA expression microarray data from RA and OA synovial fibroblasts (n=6 each). The differentially expressed genes (DEGs) in RA synovial samples compared with OA samples were identified using the Linear Models for Microarray Analysis package. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the Database for Annotation Visualization and Integrated Discovery. A protein‑protein interaction network was constructed and the modules were further analyzed using the Molecular Complex Detection plugin of Cytoscape. A total of 181 DEGs were identified by comparing RA and OA synovial samples (96 up‑ and 85 downregulated genes). The significant DEGs in module 1, including collagen, type I, α 1 (COL1A1), COL3A1, COL4A1 and COL11A1, were predominantly enriched in the extracellular matrix (ECM)‑receptor interaction and focal adhesion pathways. Additionally, significant DEGs in module 2, including radical S‑adenosyl methionine domain containing 2 (RSAD2), 2'‑5'‑oligoadenylate synthetase 2 (OAS2), myxovirus (influenza virus) resistance 1 (MX1) and ISG15 ubiquitin‑like modifier (ISG15), were predominantly associated with immune function pathways. In conclusion, the present study indicated that RSAD2, OAS2, MX1 and ISG15 may be notable gene signatures in RA development via regulation of the immune response. COL3A1, COL4A1, COL1A1 and COL11A1 may be important gene signatures in OA development via involvement in the pathways of ECM-receptor interactions and focal adhesions.