Intra-articular delivery of Si-Vangl2 limits cartilage degeneration in an osteoarthritis rat model

Osteoarthritis (OA) is driven by progressive cartilage degeneration associated with dysregulated chondrocyte metabolism and inflammatory signaling, for which effective disease-modifying treatments remain limited. In this study, we observed that Van Gogh-like 2 (Vangl2), a core component of the non-canonical Wnt/planar cell polarity (PCP) pathway, is upregulated in chondrocytes under inflammatory conditions. In a collagenase-induced OA rat model, intra-articular delivery of small interfering RNA targeting Vangl2 (Si-Vangl2) attenuated cartilage degeneration and partially preserved cartilage structure and matrix. Immunohistochemical (IHC) analysis showed that Vangl2 silencing increased the expression of anabolic and proliferative markers including Sox9, type II collagen (Col2), aggrecan, and PCNA, while reducing the levels of catabolic enzymes including matrix metalloproteinase 3 (MMP3), MMP13, as well as the hypertrophic marker type X collagen (Col10a1). Wnt5a-associated inflammatory signaling through JNK and NF-κB pathways, was also diminished following Si-Vangl2 treatment. In vitro findings suggest that Vangl2 act as a pro-chondrogenic factor, examined by real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and cell counting kit-8 (CCK-8) assays. These results indicate that Si-Vangl2 limits cartilage degeneration by enhancing anabolic activity, suppressing matrix degradation and chondrocyte hypertrophy, and restoring chondrocyte homeostasis in OA.