Background: We aimed to elucidate the molecular mechanisms underlying rheumatoid arthritis (RA) and osteoarthritis (OA) and analyze the mechanism differences between them. Methods: The gene expression profile of GSE1919, GSE12021, GSE21959 and GSE48780 were downloaded from Gene Expression Omnibus. Total 165 samples of synovial fibroblasts (118 RA samples, 15 OA samples and 32 normal controls) were used. The differentially expressed genes (DEGs) in RA samples but no differences in OA samples (RA.DEGs) and genes in OA samples but no differences in RA samples (OA.DEGs) were screened using limma package. Functional enrichment analysis was performed using DAVID. Moreover, transcriptional regulatory network (TRN) and microRNA regulatory network were constructed. Results: Total 211 RA.DEGs (96 up- and 115 down-regulate) and 497 OA.DEGs (224 up- and 273 down-regulated) were identified. TRN analysis showed that C-ETS-1 and P53 were important transcription factors. C-ETS-1 could interact with matrix metallopeptidase 1 (MMP1) and CD53 while P53 could interact with epidermal growth factor receptor (EGFR) and dual specificity phosphatase 1 (DUSP1). Besides, v-myc avian myelocytomatosis viral oncogene homolog (MYC) and interleukin 1, beta (IL1B) could be regulated by the most microRNAs in microRNA regulatory network. Our study indicates that ETS-1 may contribute to RA progression by up-regulation of MMP1 and result in OA progression via up-regulating CD53. Conclusions: P53 may be involved in the progression of RA and OA via targeting downstream EGFR and DUSP1 respectively. Besides, MYC and IL1B may play an important role in OA progression via the regulation of microRNAs. (C) 2015 Elsevier B.V. All rights reserved.