上睑下垂
软骨细胞
细胞生物学
软骨
骨关节炎
化学
炎症
分解代谢
细胞内
细胞外
生物
免疫学
医学
炎症体
病理
生物化学
解剖
替代医学
新陈代谢
作者
Taku Ebata,Mohamad Alaa Terkawi,Keita Kitahara,Shunichi Yokota,Junki Shiota,Yoshio Nishida,Gen Matsumae,Hend Alhasan,Masanari Hamasaki,Kazutoshi Hontani,Tomohiro Shimizu,Daisuke Takahashi,Tsutomu Endo,Tomohiro Onodera,Ken Kadoya,Norimasa Iwasaki
摘要
Objective The severity of osteoarthritis (OA) and cartilage degeneration is highly correlated with the development of synovitis, which is mediated by the activity of inflammatory macrophages. A better understanding of intercellular communication between inflammatory macrophages and chondrocytes should aid in the discovery of novel therapeutic targets. We undertook this study to explore the pathologic role of inflammatory macrophage extracellular vesicles (EVs) in cartilage degeneration. Methods Macrophages were stimulated by treatment with bacterial lipopolysaccharides to mimic the state of inflammatory macrophages, and the resulting EVs were harvested for chondrocyte stimulation in vitro and for intraarticular injection in a mouse model. The stimulated chondrocytes were further subjected to RNA‐sequencing analysis and other functional assays. The action of caspase 11 was disrupted in vitro using a specific small interfering RNA or wedelolactone, and in experimental murine OA models by intraarticular injection of wedelolactone. Results Stimulated chondrocytes exhibited a significant elevation in the expression of chondrocyte catabolic factors. Consistent with these results, RNA‐sequencing analyses of stimulated chondrocytes indicated that up‐regulated genes were mainly categorized into apoptotic process and tumor necrosis factor signaling pathways, which suggests the induction of apoptotic process. Moreover, these chondrocytes exhibited a significant elevation in the expression of pyroptosis‐related molecules that were correlated with the expression of chondrocyte catabolic factors. The disruption of caspase 11 significantly alleviated pyroptotic and catabolic processes in stimulated chondrocytes and pathologic changes in collagenase‐induced and joint instability–induced OA models. Conclusion Our results provide new insight into the pathologic mechanisms of OA and suggest that noncanonical pyroptosis in chondrocytes represents an attractive therapeutic target for treatment. image
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