SH2 Domain-Containing Phosphatase 2 Inhibition Attenuates Osteoarthritis by Maintaining Homeostasis of Cartilage Metabolism via the Docking Protein 1/Uridine Phosphorylase 1/Uridine Cascade
SH2 Domain-Containing Phosphatase 2 Inhibition Attenuates Osteoarthritis by Maintaining Homeostasis of Cartilage Metabolism via the Docking Protein 1/Uridine Phosphorylase 1/Uridine Cascade
复制标题
SHP2 抑制通过 DOK1/UPP1/尿苷级联维持软骨代谢的稳态，从而减轻骨关节炎
DOI：
10.1002/art.41988
复制
发表时间：
2022-02-02
影响因子：
13.3
通讯作者：
Sun, Yang
中科院分区：
文献类型：
--
作者：
Liu, Qianqian;Zhai, Linhui;Sun, Yang
目的 蛋白酪氨酸激酶通过激活一系列信号转导途径来调节骨关节炎（OA）的进展。然而，蛋白酪氨酸磷酸酶 (PTP) 在 OA 中的作用仍不清楚。本研究旨在确定 OA 中涉及的特定 PTP 并研究其潜在机制。方法基于单细胞测序数据集分析人OA软骨中107个PTP基因的表达。在白细胞介素 1 β (IL-1 β) 处理后的原代软骨细胞和人 OA 软骨中检测到含有 PTP SH2 结构域的磷酸酶 2 (SHP-2) 的酶活性。用 SHP-2 抑制剂或塞来昔布（一种用于临床治疗 OA 的药物）治疗内侧半月板 (DMM) 不稳定和 IL-1 β 刺激的小鼠原代软骨细胞的小鼠。 SHP-2在OA发病机制中的功能在Aggrecan-Cre(ERT);SHP2(flox/flox)小鼠中得到进一步验证。分别通过基于串联质量标签标记的全局蛋白质组分析和细胞培养标记的酪氨酸磷酸蛋白质组分析中的氨基酸稳定同位素标记来检查SHP-2的下游蛋白质表达谱和去磷酸化底物。结果 SHP-2 酶活性在严重关节软骨损伤的人类 OA 样本和 IL-1 β 刺激的小鼠软骨细胞中显着增加。 SHP-2 的药理学抑制或基因缺失可改善 OA 进展。 SHP-2抑制剂显着降低软骨降解相关基因的表达，同时促进软骨合成相关基因的表达。从机制上讲，SHP-2抑制抑制了对接蛋白1的去磷酸化，随后降低了尿苷磷酸化酶1的表达并增加了尿苷水平，从而有助于软骨代谢的稳态。结论 SHP-2 是一种新型的软骨稳态失衡促进剂。特异性抑制 SHP-2 可以通过维持合成代谢-分解代谢平衡来改善 OA。
Objective Protein tyrosine kinases regulate osteoarthritis (OA) progression by activating a series of signal transduction pathways. However, the roles of protein tyrosine phosphatases (PTPs) in OA remain obscure. This study was undertaken to identify specific PTPs involved in OA and investigate their underlying mechanisms. Methods The expression of 107 PTP genes in human OA cartilage was analyzed based on a single-cell sequencing data set. The enzyme activity of the PTP SH2 domain-containing phosphatase 2 (SHP-2) was detected in primary chondrocytes after interleukin-1 beta (IL-1 beta) treatment and in human OA cartilage. Mice subjected to destabilization of the medial meniscus (DMM) and IL-1 beta-stimulated mouse primary chondrocytes were treated with an SHP-2 inhibitor or celecoxib (a drug used for the clinical treatment of OA). The function of SHP-2 in OA pathogenesis was further verified in Aggrecan-Cre(ERT);SHP2(flox/flox) mice. The downstream protein expression profile and dephosphorylated substrate of SHP-2 were examined by tandem mass tag labeling-based global proteomic analysis and stable isotope labeling with amino acids in cell culture-labeled tyrosine phosphoproteomic analysis, respectively. Results SHP-2 enzyme activity significantly increased in human OA samples with serious articular cartilage injury and in IL-1 beta-stimulated mouse chondrocytes. Pharmacologic inhibition or genetic deletion of SHP-2 ameliorated OA progression. SHP-2 inhibitors dramatically reduced the expression of cartilage degradation-related genes and simultaneously promoted the expression of cartilage synthesis-related genes. Mechanistically, SHP-2 inhibition suppressed the dephosphorylation of docking protein 1 and subsequently reduced the expression of uridine phosphorylase 1 and increased the uridine level, thereby contributing to the homeostasis of cartilage metabolism. Conclusion SHP-2 is a novel accelerator of the imbalance in cartilage homeostasis. Specific inhibition of SHP-2 may ameliorate OA by maintaining the anabolic-catabolic balance.