Quercetin Suppresses Inflammation and Extracellular Matrix Degradation in Knee Osteoarthritis by Inhibiting E2F2 to Modulate SFRP5/Wnt5a Signaling

Quercetin (QUR) has been shown to ameliorate knee osteoarthritis (KOA), but its precise mechanism remains unclear. This study aimed to determine whether QUR regulates KOA by modulating E2F Transcription Factor 2 (E2F2) and elucidate the underlying mechanism. A rat anterior cruciate ligament model was established to simulate KOA. Molecular expression levels were evaluated using Reverse Transcription Quantitative Real-Time Polymerase Chain Reaction, Western blot, and immunohistochemistry. Cell viability and apoptosis were assessed using cell counting kit-8 assay and flow cytometry, respectively. E2F2 binding to secreted frizzled-related protein 5 (SFRP5) promoter was confirmed through chromatin immunoprecipitation and dual-luciferase reporter assays. Cartilage pathological damage was evaluated using hematoxylin and eosin and safranine-O/fast-green staining. QUR attenuated Interleukin-1beta-induced chondrocyte inflammation, extracellular matrix (ECM) degradation, and cartilage injury by downregulating E2F2 and inactivating the Wnt5a/Dishevelled 2 (Dvl2)/Jun N-terminal kinase (JNK) pathway. E2F2 bound the SFRP5 promoter and inhibited its transcription, whereas SFRP5 overexpression counteracted E2F2-mediated activation of the Wnt5a/Dvl2/JNK pathway. QUR suppresses chondrocyte inflammation and ECM degradation in KOA by downregulating E2F2 and modulating the SFRP5/Wnt5a/Dvl2/JNK pathway. These findings highlight the E2F2/SFRP5/Wnt5a axis as a promising therapeutic target for KOA and support the further development of quercetin as a potential treatment strategy.