Transcriptomics

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Inflammatory macrophage-derived extracellular vesicles trigger the non-canonical pyroptosis pathway in chondrocytes leading to cartilage catabolism and degeneration in osteoarthritis


ABSTRACT: The severity of osteoarthritis (OA) and cartilage degeneration are 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. Here, we explored the pathological role of inflammatory macrophage-extracellular vesicles (EVs) in cartilage degeneration. Macrophages were stimulated by treatment with bacterial lipopolysaccharides to mimic the state of inflammatory macrophages and the resulting EVs (M-LPS EVs) were harvested for chondrocyte stimulation and intraarticular injection in a mouse model. This stimulation resulted in increased catabolism of chondrocytes and cartilage degeneration. Consistently, RNA-seq analyses of stimulated chondrocytes indicated that upregulated genes are mainly categorized into apoptotic process and TNF-signaling pathway which suggests the induction of apoptotic process. 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 the pathological changes in collagenase-induced OA model. Our results provide a new insight into the pathological mechanisms of OA and suggest that non-canonical pyroptosis signaling in chondrocytes represents an attractive therapeutic target for future treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE199193 | GEO | 2023/09/20

REPOSITORIES: GEO

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