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首页> 外文期刊>European Cells & Materials >Inhibition of CDK9 prevents mechanical injury-induced inflammation, apoptosis and matrix degradation in cartilage explants
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Inhibition of CDK9 prevents mechanical injury-induced inflammation, apoptosis and matrix degradation in cartilage explants

机译：抑制CDK9可防止机械损伤引起的软骨外植体炎症，细胞凋亡和基质降解

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Joint injury often leads to post-traumatic osteoarthritis (PTOA). Acute injury responses to trauma induce production of pro-inflammatory cytokines and catabolic enzymes, which promote chondrocyte apoptosis and degrade cartilage to potentiate PTOA development. Recent studies show that the rate-limiting step for transcriptional activation of injury response genes is controlled by cyclin-dependent kinase 9 (CDK9), and thus it is an attractive target for limiting the injury response. Here, we determined the effects of CDK9 inhibition in suppressing the injury response in mechanically-injured cartilage explants. Bovine cartilage explants were injured by a single compressive load of 30 % strain at 100 %/s, and then treated with the CDK9 inhibitor Flavopiridol. To assess acute injury responses, we measured the mRNA expression of pro-inflammatory cytokines, catabolic enzymes, and apoptotic genes by RT-PCR, and chondrocyte viability and apoptosis by TUNEL staining. For long-term outcome, cartilage matrix degradation was assessed by soluble glycosaminoglycan release, and by determining the mechanical properties with instantaneous and relaxation moduli. Our data showed CDK9 inhibitor markedly reduced injury-induced inflammatory cytokine and catabolic gene expression. CDK9 inhibitor also attenuated chondrocyte apoptosis and reduced cartilage matrix degradation. Lastly, the mechanical properties of the injured explants were preserved by CDK9 inhibitor. Our results provide a temporal profile connecting the chain of events from mechanical impact, acute injury responses, to the subsequent induction of chondrocyte apoptosis and cartilage matrix deterioration. Thus, CDK9 is a potential disease-modifying agent for injury response after knee trauma to prevent or delay PTOA development.
机译：关节损伤通常会导致创伤后骨关节炎（PTOA）。对创伤的急性损伤反应诱导促炎性细胞因子和分解代谢酶的产生，从而促进软骨细胞凋亡并降解软骨以增强PTOA的发育。最近的研究表明，损伤反应基因转录激活的限速步骤受细胞周期蛋白依赖性激酶9（CDK9）的控制，因此，它是限制损伤反应的诱人靶标。在这里，我们确定了CDK9抑制作用在抑制机械损伤的软骨外植体的损伤反应中的作用。牛软骨外植体以30％的应变以100％/ s的单次压缩负荷受伤，然后用CDK9抑制剂Flavopiridol处理。为了评估急性损伤反应，我们通过RT-PCR测量了促炎细胞因子，分解代谢酶和凋亡基因的mRNA表达，并通过TUNEL染色测量了软骨细胞的活力和凋亡。对于长期结果，通过可溶性糖胺聚糖的释放以及通过确定瞬时和松弛模量的机械性能来评估软骨基质的降解。我们的数据显示CDK9抑制剂可显着降低损伤诱导的炎症细胞因子和分解代谢基因的表达。 CDK9抑制剂还减弱了软骨细胞凋亡并减少了软骨基质的降解。最后，受伤的外植体的机械性能由CDK9抑制剂保留。我们的结果提供了一个时间概况，将机械冲击，急性损伤反应等事件链与随后诱导的软骨细胞凋亡和软骨基质退化联系起来。因此，CDK9是潜在的疾病改良剂，可用于膝部创伤后的损伤反应，以预防或延迟PTOA的发展。

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