ETS2 Upregulation Facilitates Cartilage Degeneration by Targeting JUNB

Abstract

Background: The cartilage degeneration and the other changes in joint components induced by osteoarthritis (OA) can result in disability. This study aims to elucidate the underlying mechanism and explore novel treatment options for OA. Methods: The chondrocytes were treated with H₂O₂ to induce OA. The cells were transfected with small interfering RNA targeting E26 transformation-specific proto-oncogene 2 (siETS2) to investigate the role of ETS2. The viability and apoptosis in the treated cells were examined using cell counting kit-8 assay and flow cytometry, respectively. Moreover, an enzyme-linked immunosorbent assay was used to determine the levels of inflammatory factors. Cistrome was used to predict the binding interactions between Jun B proto-oncogene (JUNB) and ETS2, and Jaspar was employed to predict their binding sites. These binding interactions were validated using dual-luciferase reporter assay and chromatin immunoprecipitation analysis. Furthermore, Western blot analysis and quantitative real-time polymerase chain reaction were utilized to assess the expression levels of matrix metalloproteinase (MMP) 1/3/13, A Disintegrin and Metalloproteinase with Thrombospondin motifs 5 (ADAMTS5), ETS2, and JUNB. Results: ETS2 and JUNB expressions were upregulated in H₂O₂-induced chondrocytes (p < 0.001). ETS2 silencing promoted viability while inhibiting apoptosis, inflammation, and extracellular matrix (ECM) decomposition in H₂O₂-mediated chondrocytes (p < 0.05). However, JUNB upregulation exhibited inverse effects (p < 0.05). A binding interaction was observed between ETS2 and JUNB, suggesting a positive correlation with it. Conclusion: Our results demonstrate that ETS2 facilitates cartilage degeneration in OA by upregulating JUNB expression. This suggests that ETS2 is a novel molecular mediator of OA and a potential therapeutic target for OA intervention.