Abstract: Objective To explore the core genes and key signal pathways in the pathogenesis of knee osteoarthritis by analyzing the changes of gene expression in meniscus in patients with knee osteoarthritis (KOA). Methods mRNA expression dataset GSE45233 was downloaded from Gene Expression Omnibus (GEO) database. Then the tissue samples of patients undergoing meniscectomy due to KOA and trauma were divided into KOA group and non-KOA group. The differentially expressed genes (DEGs) of the two groups were screened. The gene function annotation and signal pathway enrichment analysis of the obtained DEGs were carried out. The protein-protein interaction (PPI) network was constructed, and the core module screening and signal pathway enrichment analysis of PPI network were carried out to find out the key signal pathways of core genes related to KOA. Results The enrichment of signal pathway showed that parathyroid hormone synthesis, secretion and activation, focal adhesion, PPAR signal pathway, chemokine signal pathway and IL-17 signal pathway may be closely related to the pathogenesis of KOA. Ten potential core genes BDNF, SNAP25, CREB1, FPR2, FYN, RTP3, IL2, OPRM1, ADCY8 and ADCY5, that may be involved in KOA were obtained by PPI network, which may be candidate genes for KOA therapy in the future. Conclusions This study identified the key signaling pathways that may be related to KOA for the first time, and screened 10 candidate core genes, which provided a new target and pathway for gene therapy of KOA.