PP2 alleviates the progression of osteoarthritis by inhibiting Wnt/β-catenin and activating TGF-β/Smad signaling

•Our data show the levels of Src, p-Src (y418) and p-FAK in knee cartilage tissue of patients with OA were abnormally increased. After chondrocytes were co-treated with IL-1β and different doses of PP2, the results showed that PP2 could reduce the abnormal increase of β-catenin, p-β-catenin and other proteins created by IL-1β and reverse the decrease of p-Smad3, Aggrecan and collagen Ⅱ proteins. Meanwhile, intraperitoneal injection of PP2 in vivo significantly reduced the degeneration of articular cartilage.•Our results also suggest that PP2 can inhibit Wnt/β-catenin and activate TGF-β/Smad signaling, thus protecting the cartilage of OA mice. We aimed to explore the effect and mechanism of the Src inhibitor PP2 on osteoarthritis (OA) progression. The protein expressions of Src, p-Src (y418) and p-FAK in normal and OA human chondrocytes were detected by immunofluorescence (IF) analysis. Chondrocytes from the femur and tibial plateau of 3-day-old mice were extracted and inoculated into 6-well plates. The chondrocytes were co-cultured with IL-1β and different doses of PP2, and then the degeneration of extracellular matrix was analyzed. A mouse OA model was induced by destabilizing medial meniscectomy of the right knee. Two weeks after the operation, different doses of PP2 were injected intraperitoneally. The drug was given three times a week for 6 weeks, and then the mice were sacrificed. Histopathological, IF and immunoblotting analyses were used to detect key OA catabolic markers and protein expression and related signaling. The levels of Src, p-Src (y418) and p-FAK in the knee cartilage tissue of patients with OA were abnormally increased. After chondrocytes were co-treated with IL-1β and different doses of PP2, the results showed that PP2 reduced the abnormal increase of β-catenin, p-β-catenin and other proteins induced by IL-1β, and reversed the decrease of p-Smad3, aggrecan and collagen Ⅱ protein levels. Meanwhile, intraperitoneal injection of PP2 in vivo significantly reduced the degeneration of articular cartilage in the OA mouse model. Our data indicate that targeting Src with PP2 protected against cartilage destruction in an OA mouse model by inhibiting Wnt/β-catenin and activating TGF-β/Smad signaling, suggesting that Src may be a potential therapeutic target for OA treatment.