Pyroptosis promotes the progression of osteoarthritis (OA). This study aims to explore the functions and regulating mechanisms of E74-like factor 3 (ELF3) in chondrocyte pyroptosis. A mouse model of OA and lipopolysaccharide (LPS)-induced chondrocytes were employed. Adenovirus sh-ELF3, miR-9-5p inhibitor or oe-Nuclear Factor kappa B subunit 1 (NFKB1) were administered to OA mice via intra-articular injection. LPS-induced chondrocytes were transfected with sh-ELF3, oe-NFKB1, miR-9-5p mimic/inhibitor or negative controls. Articular cartilage tissues were assessed using H&E staining, Safranin O/fast green staining, and Osteoarthritis Research Society International (OARSI) grading system. Pyroptosis was assessed by flow cytometry combined with Western blot analysis of key markers, while apoptosis was detected by TUNEL staining. Levels of interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) were measured by enzyme linked immunosorbent assay (ELISA). Interactions among ELF3, miR-9-5p, and NFKB1 were validated using chromatin immunoprecipitation (ChIP) and luciferase reporter assays. We found that pyroptosis was enhanced and ELF3 expression was elevated in both the OA mouse model and LPS-induced chondrocytes. Depletion of ELF3 inhibited pyroptosis, apoptosis, extracellular matrix (ECM) degeneration, and inflammation in LPS-injured chondrocytes. Mechanistically, ELF3 suppressed miR-9-5p transcription, which targeted NFKB1, and NFKB1 interacted with ELF3 to form a regulatory loop. miR-9-5p inhibition or NFKB1 overexpression reversed the protective effects of ELF3 knockdown on pyroptosis and ECM degradation. In vivo study further confirmed that silencing ELF3 attenuated articular cartilage injury through miR-9-5p/NFKB1/ NLR Family Pyrin Domain Containing 3 (NLRP3) axis. Overall, the ELF3/miR-9-5p/NFKB1 axis accelerated OA progression by promoting NLRP3-mediated chondrocyte pyroptosis.
Gong et al. (Fri,) studied this question.