〔Abstract〕 Objective To investigate the mechanism of estrogen mediated chondrocyte secretion of inflammatory cytokines. Methods Patients with femoral neck fracture admitted to Shenzhen Second People's Hospital were collected, and the femoral head was sterile removed during hip replacement, and the articular chondrocytes were isolated and cultured. Only chondrocyte culture medium was added to the blank control group. In addition to chondrocyte culture medium, estradiol (E2), estrogen receptor α (ERα), estrogen receptor β (ERβ) and estrogen receptor blocker fluvestrant (Ful) were added to the other observation groups, and cultured for 48 h, compared with the blank control group. By analyzing GSH-IN-3 chip chondrocytes secretion of the inflammatory factor, enrichment of signaling pathways in DAVID website (https://david.ncifcrf.gov/) gene ontology (GO) and the Kyoto encyclopedia genome and genomes (KEGG) analysis, to elucidate the key genes and molecular markers of estrogen regulation of chondrocyte expression. Results Compared with the blank control group, different protein expressions were identified in all groups in the observation group. The target genes were screened through protein profiling. When estrogen mediated chondrocyte secretion of validation factors, the up-regulated genes included: interleukin (IL) -1α, IL-5, IL-11, intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor (TNF) -RI, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12P70, tissue inhibitor of metalloproteinase (TIMP)-1, and macrophage inflammatory protein (MIP)-1β. Down-regulated genes included B lymphocyte chemokine (BLC), monocyte colony stimulating factor (MCSF), monocyte chemokine protein-1 (MCP-1), IL-17, IL-2, IL-4, TNF-α and IL-8. GO analysis showed that differential genes were mainly concentrated in cytokine-mediated signaling pathways, endoplasmic reticulum lumen, signaling receptor activator activity and receptor ligand activity. KEGG analysis showed that cytokine activity, cytokine-cytokine receptor interactions, and the rheumatoid arthritis pathway were involved in estrogen activation of chondrocyte inflammatory factors. Conclusion Estrogen mainly up-regulates IL-5, IL-11, TNF-RI, ICAM-1, and IL-1α, which are key genes of chondrocyte secretion factors through cytokine activity and cytokine-cytokine receptor interactions, and may be potential therapeutic targets for osteoarthritis (OA).