探究EGR1在骨关节炎病理发展中的作用机制及治疗意义

Osteoarthritis is one of the most common orthopedic diseases in which elderly people lose their mobility. Although the pathogenesis of osteoarthritis remains unclear, the degradation of cartilage matrix and the abnormal hypertrophy of chondrocytes are considered as common pathological changes and the most important pathogenic mechanisms of osteoarthritis. Our previous data suggest that EGR1 is abnormally highly expressed in articular cartilage of patients with osteoarthritis. In the natural degeneration process of bone and joint in mice (February, June and December) and osteoarthritis model, EGR1 gene expression and chondrocyte hypertrophy showed a positive correlation. We found that stimulation of IL-1 induced the expression of EGR1 in chondrocytes. While ML264, an inhibitor of EGR1 / KLF5, significantly inhibited IL-1-mediated degradation of the cartilage matrix. In vivo experiments showed that ML264 can significantly protect the mouse joint from degradation of the articular cartilage matrix. The project will use cytology, molecular biology and other means, the use of EGR1 knockout mice to to investigate the dual role of EGR1 in the degradation of chondrocytes and the abnormal hypertrophy of chondrocytes. This project provides a theoretical basis for alleviating the pathological progress of osteoarthritis and clarifying its pathogenesis

骨关节炎是中老年人失去活动能力最常见的骨科疾病之一。尽管骨关节炎的发病机制尚不明确，但是软骨基质的降解与软骨细胞的异常肥大被认为是骨关节炎常见的病理变化和最主要的致病机制。我们前期的研究数据表明，骨关节炎患者关节软骨中EGR1有着异常的高表达。而在小鼠骨关节自然退变过程（2月、6月、12月）与骨关节炎造模中，EGR1基因的表达与软骨细胞肥大呈现正相关的关系。我们发现IL-1刺激下，能诱导软骨细胞EGR1的表达。而EGR1/KLF5的抑制剂ML264能够明显抑制IL-1介导的软骨基质的降解。体内实验表明，ML264能够显著抑制小鼠关节炎的关节软骨基质的降解。本项目将通过细胞学、分子生物学等手段，应用EGR1敲除小鼠，探讨EGR1在软骨细胞基质降解与软骨细胞异常肥大中的双重作用。为缓解骨关节炎病理进展及明确其发病机制提供理论依据。

骨性关节炎是常见的慢性退行性骨关节病，具有明显的年龄相关性。由于其高发病率，对社会健康、经济成本以及个人日常活动和生活质量产生重大影响。年龄在骨关节炎疾病进展中被认为是最主要的高危因素，但是其具体的病理机制依旧不明。. 本项目从疾病的发生发展入手，探寻同时调控骨关节炎过程中软骨基质降解以及软骨细胞异常肥大的机制，为明确骨关节炎疾病机理以及治疗骨关节炎提供理论依据。我们发现EGR1在人体以及小鼠多个骨关节炎模型中异常高表达。炎症环境刺激了EGR1的基因表达，同时EGR1的过表达同样造成了软骨细胞基质的降解。而敲除EGR1的表达之后，炎症刺激介导的软骨基质降解得到了挽救。进一步研究我们发现，EGR1同样调控着软骨细胞的肥大，伴随着软骨细胞肥大相关蛋白的表达。免疫共沉淀实验进一步揭示EGR1通过调控KLF5蛋白的表达，进而调控软骨基质的降解。而β-catenin 信号通路在EGR1调控软骨细胞肥大过程中发挥功能。小鼠体内实验进一步证实EGR1参与调控小鼠骨关节炎疾病的进展。而有意思的是，EGR1的抑制剂ML264证实可以参与挽救骨关节炎的疾病进展，为临床转化提供了有力的依据。. 对于骨关节炎疾病的探究一直是基础研究的热点，机制研究联合小分子化合物的治疗，为基础与临床之间搭建了桥梁。

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