Sirtuin 2 regulates NOD-like receptor protein 3/nuclear factor kappa B axis to promote cartilage repair in osteoarthritis

Abstract

Osteoarthritis (OA) is a prevalent degenerative joint disease driven by inflammation and cartilage degradation. The NOD-like receptor protein 3 (NLRP3) inflammasome and nuclear factor kappa B (NF-κB) pathway are central to OA-associated inflammation. Sirtuin 2 (SIRT2), an NAD⁺-dependent deacetylase, regulates inflammation and oxidative stress but its role in OA is not fully understood. This study aims to elucidate how SIRT2 modulates the NLRP3/NF-κB signaling axis to promote cartilage repair in OA. In vivo and in vitro experiments were conducted using OA mouse models and chondrocyte cultures. Single-cell RNA sequencing was performed to identify differentially expressed genes, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. SIRT2's impact on NLRP3 and NF-κB was assessed using Western blotting (WB), real-time PCR, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP-qPCR). SIRT2 was found to deacetylate NF-κB p65, inhibiting NLRP3 activation and reducing inflammatory cytokines. SIRT2 overexpression enhanced chondrocyte proliferation, DNA repair, and mitochondrial function while decreasing reactive oxygen species production. In vivo, SIRT2 significantly improved cartilage repair in OA mice with NLRP3 overexpression attenuating its protective effects. SIRT2 promotes cartilage repair in OA by regulating the NF-κB/NLRP3 axis, reducing inflammation and oxidative stress. This highlights SIRT2 as a potential therapeutic target for OA.