Knee osteoarthritis (KOA) is a chronic, degenerative disease that affects not only the bone and cartilage but also all periarticular soft tissues. Transcriptomic investigations in osteoarthritis have recently advanced due to the introduction of RNA sequencing, which has been used to elucidate significant molecular differences between groups of patients with KOA. A total of 29 patients with knee pain were selected and divided into two groups. Group 1 comprised 26 patients, who were diagnosed with stage four KOA according to the Kellgren and Lawrence (KL) classification and were scheduled for total knee arthroplasty. Group 2 consisted of three patients who constituted the control group. The main objective of this study is to analyze gene expression in suprapatellar synovial tissue using the RT-PCR technique in patients with knee osteoarthritis. The promising results of gene expression analysis highlight the complex transcriptomic profile of synovial tissue in patients with stage IV KL KOA who required TKA after conservative treatments failed. The analysis of the expression of four genes indicates that compensatory mechanisms are either insufficient or exhausted due to the chronic proinflammatory status. Pro-inflammatory transcription factors (JUN, MYC) and feedback regulators (DUSP1, NFKBIA) require extensive clinical trials for the use of disease-modifying drugs.