Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Promotes Inflammation and Accelerates Osteoarthritis by Activating β-Catenin.
Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Promotes Inflammation and Accelerates Osteoarthritis by Activating β-Catenin.
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DOI：
10.3389/fcell.2021.646386
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发表时间：
2021
影响因子：
5.5
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Tao T;Luo D;Gao C;Liu H;Lei Z;Liu W;Zhou C;Qi D;Deng Z;Sun X;Xiao J
骨关节炎是一种以软骨退化、软骨下骨改建和骨赘形成为特征的慢性关节疾病。SRC同源2含结构域蛋白酪氨酸磷酸酶(SHP2)在骨性关节炎发病机制中的作用尚未得到充分研究。在本研究中，我们发现经IL-1β(IL-1β)处理的原代小鼠软骨细胞SHP2的表达显著增加。用siRNA抑制SHP2在体外可降低MMP3、MMP13的表达，而增加AGGRECAN、COL2A1、SOX9的表达。相反，SHP2的过度表达起到了相反的作用，促进了软骨的降解。机制上，SHP2可能通过直接与β-连环蛋白结合来激活Wnt/β-连环蛋白信号。Shp2还通过激活丝裂原活化蛋白激酶和核因子κB(NF-κB)途径诱导炎症反应。我们的体内研究表明，SHP2基因敲除有效地延缓了由内侧半月板失稳(DMM)诱导的小鼠OA模型的软骨破坏和骨赘形成。综上所述，我们的研究确定SHP2是一个新的和潜在的治疗OA的靶点。
Osteoarthritis (OA) is a chronic articular disease characterized by cartilage degradation, subchondral bone remodeling and osteophyte formation. Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) has not been fully investigated in the pathogenesis of OA. In this study, we found that SHP2 expression was significantly increased after interleukin-1β (IL-1β) treatment in primary mouse chondrocytes. Inhibition of SHP2 using siRNA reduced MMP3, MMP13 levels, but increased AGGRECAN, COL2A1, SOX9 expression in vitro. On the contrary, overexpression of SHP2 exerted the opposite results and promoted cartilage degradation. Mechanistically, SHP2 activated Wnt/β-catenin signaling possibly through directly binding to β-catenin. SHP2 also induced inflammation through activating Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Our in vivo studies showed that SHP2 knockdown effectively delayed cartilage destruction and reduced osteophyte formation in the mouse model of OA induced by destabilization of the medial meniscus (DMM). Altogether, our study identifies that SHP2 is a novel and potential therapeutic target of OA.
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影响因子：
4.8
作者：
Ming, Ming;Wang, Sheng;Qian, Zhijian
通讯作者：
Qian, Zhijian
影响因子：
16.6
作者：
Niogret, Charlene;Miah, S. M. Shahjahan;Guarda, Greta
通讯作者：
Guarda, Greta
DOI：
10.3109/17453679509157660
发表时间：
1995-10-01
期刊：
ACTA ORTHOPAEDICA SCANDINAVICA
影响因子：
--
作者：
Lark, MW;Bayne, EK;Lohmander, LS
通讯作者：
Lohmander, LS
影响因子：
4.6
作者：
Stickens, D;Behonick, DJ;Werb, Z
通讯作者：
Werb, Z
影响因子：
8.8
作者：
Sturla, L-M;Zinn, P. O.;Ng, K.;Nitta, M.;Kozono, D.;Chen, C. C.;Kasper, E. M.
通讯作者：
Kasper, E. M.