Chondrocyte lysates (CLs) were found to significantly enhance inflammatory responses in fibroblast-like synoviocytes (FLSs).
FLSs engulfed CLs, leading to increased release of inflammatory cytokines.
NLRP3 expression was significantly higher in human OA-FLSs and in FLSs cocultured with CLs.
Overexpression of (CAV1) reversed the inflammatory effects in FLSs and reduced in CL-pre-treated FLSs.
In a mouse model, intra-articular injection of AAV-CAV1 alleviated synovial hyperplasia and inflammation following medial meniscus destabilization.
The CL-specific protein LIM-containing lipoma preferred partner (LPP) was associated with increased FLS pyroptosis and inflammation.
Simplified
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 (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 -mediated .
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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Declarations. Ethics approval and consent to participate: All experiments involving animal and patient samples in this study adhered to ethical policies and procedures approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-Sen University, China. (Approval no. IRB: IIT-2021-667; SYSU-IACUC-2020-000504). Consent for publication: Written informed consent for publication was obtained from all participants. Competing interests: The authors declare no competing interests.
PubMed
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