The Annexin A1 Protein Mimetic Peptide Ac2-26 prevents cellular senescence of CHON-001 chondrocytes against tumor necrosis factor-α via the Nrf2/NF-κB pathway

Osteoarthritis (OA) is a degenerative joint disorder characterized by progressive cartilage degradation. Excessive oxidative stress (OS), inflammatory responses, extracellular matrix breakdown, and cellular senescence of chondrocytes play crucial roles in the pathological development of OA. Currently, curing OA remains a significant challenge. In this study, we aimed to elucidate the protective effects of Annexin A1 protein Mimetic Peptide (Ac2-26) against tumor necrosis factor-alpha (TNF-alpha)-induced damage in CHON-001 chondrocytes by assessing cellular senescence, OS, and the expression levels of matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4. Our results show that Ac2-26 mitigated the reduction of telomerase activity and the exacerbation of cellular senescence induced by TNF-alpha in CHON-001 chondrocytes. Treatment with TNF-alpha led to decreased expression of the human telomerase reverse transcriptase gene and increased expression of the telomeric repeat-binding factor 2 gene, which were reversed by Ac2-26 treatment. The TNF-alpha-induced increases in the gene and protein expressions of p53 and p16 were restored by Ac2-26 in a dose-dependent manner. Additionally, we found that TNF-alpha caused elevations in the mRNA and protein levels of MMP-13 and ADAMTS-4, which were reduced by Ac2-26 in a dose-dependent fashion. Furthermore, TNF-alpha triggered the activation of nuclear factor kappa-B (NF-kappa B) by increasing the levels of phosphorylated NF-kappa B p65 and the luciferase activity of NF-kappa B. Notably, Ac2-26 alleviated OS by reducing mitochondrial reactive oxygen species levels and promoting the activation of NF-E2-related factor 2 (Nrf2) in TNF-alpha-challenged CHON-001 chondrocytes. Silencing Nrf2 abolished the Ac2-26-induced activation of NF-kappa B and cellular senescence in CHON-001 chondrocytes. Collectively, these findings offer new insights into the potential therapeutic use of Ac2-26 for treating OA.