EGR1 promotes the cartilage degeneration and hypertrophy by activating the Kruppel-like factor 5 and β-catenin signaling
EGR1 promotes the cartilage degeneration and hypertrophy by activating the Kruppel-like factor 5 and β-catenin signaling
复制标题
EGR1 通过激活 Kruppel 样因子 5 和 β-catenin 信号传导促进软骨退化和肥大
DOI：
10.1016/j.bbadis.2019.06.010
复制
发表时间：
2019-09-01
影响因子：
6.2
通讯作者：
Shi, Peihua
中科院分区：
文献类型：
--
作者：
Sun, Xuewu;Huang, Hai;Shi, Peihua
骨性关节炎是老年人失去行动能力最常见的骨科疾病之一。在这项研究中，我们观察到骨关节炎患者关节软骨中Egr1的异常高表达。我们还发现，在内侧半月板失稳(DMM)诱导的骨关节炎小鼠和20月龄小鼠的关节软骨中，Egr1的表达显著增加。体外实验表明，IL-1β可显著增强原代小鼠软骨细胞Egr1的表达。腺病毒介导的软骨细胞Egr1过表达可抑制CO12A1的表达，增强MMP9和MMP13的表达。而使用RNAi沉默Egr1则产生了相反的效果。此外，Egr1过表达可加速体外培养的软骨细胞肥大，Egr1基因敲除可逆转这一作用。然后，我们探索了潜在的机制。Egr1过表达可增加Kruppel样因子5(KLF5)蛋白水平，但不影响KLF5的合成。增强的Egr1表达诱导其与KLF5整合，导致KLF5泛素化受到抑制。此外，Egr1还促进了β-连环蛋白的核转运，以控制软骨细胞的肥大。Egr1在关节软骨中的异位表达加剧了体内软骨基质的降解。EGR1抑制剂ML264在体外保护软骨细胞免受IL-1β介导的软骨基质降解和体内DMM诱导的骨关节炎的影响。综上所述，我们展示了EGR1对骨性关节炎的作用和机制，并为ML264可能成为未来治疗骨性关节炎的潜在药物提供了证据。
Osteoarthritis is one of the most common orthopedic diseases in elderly people who have lost their mobility. In this study, we observed abnormally high EGR1 expression in the articular cartilage of patients with osteoarthritis. We also found significantly high EGR1 expression in the articular cartilage of mice with destabilized medial meniscus (DMM)-induced osteoarthritis and 20-month-old mice. In vitro experiments indicated that IL-1 beta could significantly enhance EGR1 expression in primary mouse chondrocytes. EGR1 over-expression in chondrocytes using adenovirus could inhibit COl2A1 expression and enhance MMP9 and MMP13 expression. And silencing EGR1, using RNAi, had the opposite effects. Moreover, EGR1 over-expression accelerated chondrocyte hypertrophy in vitro, and EGR1 knockdown reversed this effect. We then explored the underlying mechanism. EGR1 over-expression increased Kruppel-Like Factor 5 (KLF5) protein level without influencing its synthesis. Enhanced EGR1 expression induced its integration with KLF5, leading to suppressed ubiquitination of KLF5. Moreover, EGR1 prompted beta-catenin nuclear transportation to control chondrocyte hypertrophy. Ectopic expression of EGR1 in articular cartilage aggravated the degradation of the cartilage matrix in vivo. The EGR1 inhibitor, ML264, protected chondrocytes from IL-1 beta-mediated cartilage matrix degradation in vitro and DMM-induced osteoarthritis in vivo. Above all, we demonstrate the effect and mechanisms of EGR1 on osteoarthritis and provide evidence that the ML264 might be a potential drug for treating osteoarthritis in the future.