WRG-28 attenuates matrix degradation and chondrocyte calcification by inhibiting DDR2 signaling in osteoarthritis.

Osteoarthritis (OA) is a common degenerative joint disease characterized by cartilage degradation and abnormal bone remodeling. Discoidin Domain Receptor 2 (DDR2) has emerged as a critical mediator of OA pathogenesis by disrupting extracellular matrix (ECM) homeostasis. This study investigates the therapeutic potential of DDR2 inhibition via selective allosteric inhibitor WRG-28. To evaluate its in vivo efficacy, an OA rat model was established, followed by intra-articular injections of WRG-28. The therapeutic effects were assessed using μCT, Safranin O/Fast Green staining, immunohistochemistry, and gait analysis. Furthermore, primary chondrocytes were stimulated with Type II collagen (Col II) in vitro, followed by immunofluorescence and qPCR to elucidate the underlying molecular mechanisms. Results showed that WRG-28 significantly attenuated osteophyte formation and cartilage degradation in vivo. Treated OA cartilage exhibited preserved Col II content, alongside suppressed DDR2 activation and reduced expression of matrix metalloproteinase 13 (MMP13). Consistent with these findings, in vitro experiments showed that WRG-28 effectively inhibited DDR2 activation in chondrocytes, leading to downregulated MMP expression and restored levels of cartilage matrix-related genes. Additionally, WRG-28 treatment prevented abnormal chondrocyte calcification. In summary, this study concludes that WRG-28 prevents cartilage degradation and inhibits abnormal chondrocyte calcification by targeting DDR2 activation, offering a novel approach to alleviate the progression of OA.