Noncanonical Pyroptosis Triggered by Macrophage‐Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis

Abstract

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.

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1

“…They mediate proximal or distal cellular communication by transporting a variety of functional substrates associated with tissue homeostasis and disease [ 15 , 16 ]. Recent research showed that macrophage-derived EVs led to cartilage catabolism and synovial inflammation, supporting the important role of EVs in OA [ 17 ]. Furthermore, synovial fibroblasts delivered microRNAs(miRNAs) to chondrocytes through EVs to mediate chondrocyte function, indicating that the EVs delivery function may be a potential mechanism in OA progression [ 18 ].…”

From drugs to biomaterials: a review of emerging therapeutic strategies for intervertebral disc inflammation

“…The phospholipid bilayer on their surface exhibits recognition specificity, making EVs well-suited for precise biological marking and the transport of certain drugs ( Jeppesen et al., 2023 ). EVs represent an emerging field of research in skeletal repair, with the majority of published studies emerging within the last five years ( Yin et al., 2022 ; Ebata et al., 2023 ; Liu et al., 2023c ). Documentation of the efficacy of EVs in various organs and systems exists, and in osteoarthritis (OA), it has been observed that EVs derived from mesenchymal stem cells (MSCs) can inhibit inflammation, downregulate the levels of IL-1β, IL-6, and IL-8, and increase extracellular matrix synthesis, effectively alleviating pain ( Li et al., 2022 ).…”

Pyroptosis in Osteoarthritis: Molecular Mechanisms and Therapeutic Implications

“…M2 macrophages can turn into M1 macrophages, which cause inflammation. 73 In individuals with OA, macrophages deposit crystals in the synovium. Dead cells release ATP, which activates the NLRP3 inflammasome to produce IL-1β and IL-18.…”

“…It has been discovered through research that the inflammatory extracellular vesicles from macrophages can trigger both canonical and non-canonical pyroptosis in chondrocytes, leading to cartilage breakdown. 73 , 80 , 81 The synovium plays a crucial role in providing essential nutrition to the avascular cartilage tissue, and synovitis, the inflammation of the synovial tissue, is a significant factor in the development of OA. When the synovial tissue undergoes pyroptosis, it releases pro-inflammatory cartilage degradation products into the synovial fluid, which causes inflammation in the surrounding synovium, leading to further degradation of chondrocytes.…”

“…Numerous studies have delved into the role of NLRP3 inflammasome in canonical pyroptosis, while only a few have explored non-canonical or alternative pyroptosis. 73 The current limitations make it difficult to create animal models of non-canonical or alternative pyroptosis and identify the activators that cause pyroptosis in vitro. Although pyroptosis of synovial macrophages, FLS, and chondrocytes is believed to play a role in OA development, the exact function of pyroptosis remains contested due to variations in animal models and stimuli.…”