Chondrocyte lysates activate NLRP3 inflammasome-induced pyroptosis in synovial fibroblasts to exacerbate knee synovitis by downregulating caveolin-1
Abstract Background Synovitis, among the most common signs of early-stage osteoarthritis (OA), is mainly mediated by fibroblast-like synoviocytes (FLSs). Cartilage destruction creates chondrocyte lysates (CLs) that activate synovial inflammation. A comprehensive understanding of chondrocyte–FLS comm...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13075-025-03573-0 |
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| Summary: | Abstract Background Synovitis, among the most common signs of early-stage osteoarthritis (OA), is mainly mediated by fibroblast-like synoviocytes (FLSs). Cartilage destruction creates chondrocyte lysates (CLs) that activate synovial inflammation. A comprehensive understanding of chondrocyte–FLS communication might offer novel, specific therapeutic targets for treating synovitis and OA. Hence, we sought to uncover the specific role of CLs in OA-FLSs and synovitis. Methods Isolated CLs were cocultured with FLSs to test whether they could stimulate synovial inflammation. A model of medial meniscus destabilization was prepared in C57BL/6 mice and NLRP3 knockout mice, and adeno-associated virus overexpressing Caveolin-1 (CAV1) was intra-articularly injected for 8 weeks once a week after dissection of the medial meniscus (DMM). Proteins expressed in FLSs with and without CL coculture were screened using liquid chromatography-tandem mass spectrometry to identify CL-specific regulators of NLRP3 inflammasome-mediated pyroptosis. Results CLs were engulfed by FLSs, which aggravated inflammatory cytokine release and NLRP3 inflammasome-mediated FLS pyroptosis. NLRP3 expression was significantly upregulated in human OA-FLSs and FLSs cocultured with CLs, while CAV1 was downregulated. CAV1 overexpression reversed the inflammatory phenotype in FLSs and simultaneously rescued pyroptosis in CL-pre-treated FLSs. Both synovial hyperplasia and inflammatory infiltration in C57BL/6 mice with DMM surgery were alleviated after intra-articular AAV-CAV1 injection. Moreover, the CL-specific protein LIM-containing lipoma preferred partner (LPP) markedly exacerbated FLS pyroptosis and inflammation. Conclusions CLs were endocytosed by FLSs through CAV1, and the CL-specific protein LPP stimulated NLRP3 inflammasome-mediated pyroptosis and synovitis by inhibiting CAV1 expression. Our findings offer a novel therapeutic target for treating synovitis. |
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| ISSN: | 1478-6362 |