ABSTRACT. Peroxisome proliferator-activated receptor is closely associated with the pathogenesis of osteoarthritis. The level of exogenous advanced glycation end-products (AGEs) in articular cartilage is highly associated with the severity of osteoarthritic lesions. However, their interactions and role in promoting osteoarthritisprogression remain unclear. Here, we investigated the effect of AGEs on transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 expression, and discussed the correlation between AGEs and osteoarthritis, possible signaling pathways and mechanism in rabbit chondrocytes. TGF-β and MMP-9 mRNA and protein expression, catalase (CAT) and superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and reactive oxygen species (ROS) levels were analyzed in chondrocytes treated with different concentrations of AGEs using RT-PCR and/or western blot; we detected NF-κB nuclear translocation by immunofluorescence. AGE treatment significantly increased TGF-β and MMP-9 mRNA and protein expression compared to controls (P < 0.01) in a dose-dependent manner (highest at 100 µg/mL). AGE-induced TGF-β and MMP-9 expressions in chondrocytes were significantly inhibited by anti-RAGE and PDTC (0.1 mM) treatment (P < 0.01). Furthermore, AGE-treatment significantly decreased CAT and SOD activity and increased MDA levels in a concentration-dependent manner compared to controls (P < 0.05), significantly promoting NF-κB nuclear translocation. AGE significantly inhibited the increased expression of TGF-β and MMP-9, and induced chondrocyte damage. Its mechanism is associated with RAGE activation, increased ROS expression, and activation of the NF-κB signaling pathways.
Foxa2 is one member of the Foxa subfamily of winged helix/forkhead box (Fox) transcription factors which has been found to play important roles in multiple stages of mammalian life, beginning with early development, continuing during organogenesis, and finally in metabolism and homeostasis in the adult. To explore the involvement of Foxa2 and its epigenetic regulations in cellular senescence, we established the premature senescence model induced by hydrogen peroxide in comparison with replicative senescence. The mRNA level of Foxa2 was downregulated in both replicative and premature senescent cells. We further found the increased DNA methylation level and new methylation at CpG sites in the promoter with 43.6% of methylated CpG islands in premature senescence, while only 5.7% and 17.1% in young cells and replicative senescence separately. Moreover, we noted the alterations of histone modifications including decreased histone H3 acetylation, increased H4 (Lys-20) trimethylation at the Foxa2 CpG islands in the promoter in replicative or premature senescence, while decreased histone H3 (Lys-4) trimethylation across the transcription start regions in cellular senescence. Taken together, epigenetic silencing of Foxa2 is associated with an increased DNA methylation level and histone H4 (Lys-20) trimethylation, decreased histone H3 acetylation and histone H3 (Lys-4) trimethylation, involved in cellular replicative or premature senescence.
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