Lehtola Tiina, Nummenmaa Elina, Tuure Lauri, Hämäläinen Mari, Nieminen Riina M, Moilanen Teemu, Pemmari Antti, Moilanen Eeva
The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, 33014 Tampere, Finland.
Coxa Hospital for Joint Replacement, 33520 Tampere, Finland.
Int J Mol Sci. 2022 Mar 31;23(7):3880. doi: 10.3390/ijms23073880.
Mitogen-activated protein kinase phosphatase-1 (MKP-1) is upregulated in inflammation and reduces the activity of proinflammatory mitogen-activated protein kinases (MAP kinases) by dephosphorylation. MAP kinases are intracellular signaling pathways that mediate the cellular effects of proinflammatory cytokines. In the present study, we investigated the effects of the glucocorticoid dexamethasone on the expression of catabolic enzymes in chondrocytes and tested the hypothesis that these effects are mediated through MKP-1. Dexamethasone was found to significantly attenuate the expression of matrix metalloproteinase (MMP)-13 in human OA chondrocytes as well as in chondrocytes from MKP-1 WT mice, but not in chondrocytes from MKP-1 KO mice. Dexamethasone also increased the expression of MKP-1 in murine and human OA chondrocytes. Furthermore, p38 MAP kinase inhibitors significantly attenuated MMP-13 expression in human OA chondrocytes, while JNK MAP kinase inhibitors had no effect. The results indicate that the effect of dexamethasone on MMP-13 expression in chondrocytes was mediated by an MKP-1 and p38 MAP kinase-dependent manner. These findings, together with previous results, support the concept of MKP-1 as a protective factor in articular chondrocytes in inflammatory conditions and as a potential drug target to treat OA.
丝裂原活化蛋白激酶磷酸酶-1（MKP-1）在炎症中上调，并通过去磷酸化降低促炎丝裂原活化蛋白激酶（MAP激酶）的活性。MAP激酶是介导促炎细胞因子细胞效应的细胞内信号通路。在本研究中，我们研究了糖皮质激素地塞米松对软骨细胞中分解代谢酶表达的影响，并测试了这些影响是通过MKP-1介导的这一假设。发现地塞米松可显著减弱人骨关节炎（OA）软骨细胞以及MKP-1野生型小鼠软骨细胞中基质金属蛋白酶（MMP）-13的表达，但对MKP-1基因敲除小鼠的软骨细胞没有影响。地塞米松还增加了小鼠和人OA软骨细胞中MKP-1的表达。此外，p38 MAP激酶抑制剂可显著减弱人OA软骨细胞中MMP-13的表达，而JNK MAP激酶抑制剂则没有作用。结果表明，地塞米松对软骨细胞中MMP-13表达的影响是以MKP-1和p38 MAP激酶依赖性方式介导的。这些发现与先前的结果一起，支持了MKP-1作为炎症条件下关节软骨细胞中的保护因子以及作为治疗OA的潜在药物靶点的概念。
