OBJECTIVE: Protein tyrosine kinases regulate osteoarthritis (OA) progression byactivating a series of signal transduction pathways. However, the roles ofprotein tyrosine phosphatases (PTPs) in OA remain obscure. This study wasundertaken to identify specific PTPs involved in OA and investigate theirunderlying mechanisms.METHODS: The expression of 107 PTP genes in human OA cartilage was analyzedbased on a single-cell sequencing data set. The enzyme activity of the PTP SH2domain-containing phosphatase 2 (SHP-2) was detected in primary chondrocytesafter interleukin-1尾 (IL-1尾) treatment and in human OA cartilage. Mice subjectedto destabilization of the medial meniscus (DMM) and IL-1尾-stimulated mouseprimary chondrocytes were treated with an SHP-2 inhibitor or celecoxib (a drugused for the clinical treatment of OA). The function of SHP-2 in OA pathogenesiswas further verified in Aggrecan-CreERT ;SHP2flox/flox mice. The downstreamprotein expression profile and dephosphorylated substrate of SHP-2 were examinedby tandem mass tag labeling-based global proteomic analysis and stable isotopelabeling with amino acids in cell culture-labeled tyrosine phosphoproteomicanalysis, respectively.RESULTS: SHP-2 enzyme activity significantly increased in human OA samples withserious articular cartilage injury and in IL-1尾-stimulated mouse chondrocytes.Pharmacologic inhibition or genetic deletion of SHP-2 ameliorated OAprogression. SHP-2 inhibitors dramatically reduced the expression of cartilagedegradation-related genes and simultaneously promoted the expression ofcartilage synthesis-related genes. Mechanistically, SHP-2 inhibition suppressedthe dephosphorylation of docking protein 1 and subsequently reduced theexpression of uridine phosphorylase 1 and increased the uridine level, therebycontributing to the homeostasis of cartilage metabolism.CONCLUSION: SHP-2 is a novel accelerator of the imbalance in cartilagehomeostasis. Specific inhibition of SHP-2 may ameliorate OA by maintaining theanabolic-catabolic balance.
School of Life Sciences, Nanjing University
Nanjing 210023, China