SHP2 inhibition attenuates osteoarthritis by maintaining homeostasis of cartilage metabolism via the DOK1/UPP1/uridine cascade

Objective Protein tyrosine kinases (PTKs) regulate osteoarthritis (OA) progression by activating a series of signal transduction pathways. However, the roles of protein tyrosine phosphatases (PTPs) in OA remain obscure. Methods The expression of 107 PTP genes in human OA cartilage was analyzed based on a single-cell sequencing dataset. The enzyme activity of the PTP SHP2 was detected in primary chondrocytes after interleukin (IL)-1β treatment and in human OA cartilage. Destabilized medial meniscus (DMM) model and IL-1β-stimulated primary mouse chondrocytes were treated with an SHP2 inhibitor and celecoxib (a clinical drug for the treatment of OA). The function of SHP2 in OA pathogenesis was further verified in Aggrecan-CreERT ; SHP2 flox/flox mice. The downstream protein expression profile and dephosphorylated substrate of SHP2 were examined by tandem mass tag (TMT) labeling-based global proteomic and stable isotope labeling using amino acids in cell culture (SILAC)-labeled tyrosine phosphoproteomic analysis, respectively. Results SHP2 enzyme activity significantly increased in human OA samples with serious articular cartilage injury and in IL-1β-stimulated chondrocytes. Pharmacological inhibition or genetic deletion of SHP2 ameliorated OA progression. SHP2 inhibitors dramatically reduced the expression of cartilage degradation-related genes and simultaneously promoted the expression of cartilage synthesis-related genes. Mechanistically, SHP2 inhibition suppressed the dephosphorylation of DOK1 and subsequently reduced the expression of uridine phosphorylase 1 and increased uridine level, thereby contributing to the homeostasis of cartilage metabolism. Conclusions SHP2 is a novel accelerator of the imbalance in the cartilage homeostasis. Specific inhibition of SHP2 may ameliorate OA by maintaining the anabolic and catabolic balance.