Glutaredoxin-1 (GRX-1), belonging to the oxidoreductase family, is a component of the endogenous antioxidant defense system. In this study, we evaluated the effects of PEP-1-GRX-1 in rabbit articular chondrocytes. We found that PEP-1-GRX-1 causes a loss of the differentiated chondrocyte phenotype. PEP-1-GRX-1-treated cells exhibited decreases in type II collagen expression and sulfated-proteoglycan synthesis in a dose- and time-dependent manner. PEP-1-GRX-1 causes endoplasmic reticulum (ER)-stress, as evidenced by increases in ER stress marker proteins, i.e., glucose-regulated protein (GRP) 78, GRP 94, and phospho-eukaryotic initiation factor 2 (eIF2) α. These effects were inhibited by ER stress inhibitors. PEP-1-GRX-1 increased the phosphorylation of Akt, extracellular signal-regulated kinase (ERK)-1/2, and p38. Inhibition of ERK-1/2 by PD98059 prevented PEP-1-GRX-1-induced dedifferentiation and inhibited ER stress. The blockage of PI-3K/Akt or p38 kinase with SB203580 and LY294002 accelerated PEP-1-GRX-1-induced dedifferentiation, but did not have any effect on PEP-GRX-1-induced ER stress. Our results indicate that the ERK-1/2 pathway mediates chondrocyte dedifferentiation by PEP-GRX-1-induced ER stress. The PI-3K and p38 kinase pathways regulate PEP-1-GRX-1-induced chondrocyte dedifferentiation by an ER stress-independent pathway.
Pubmed ID: 29366902 RIS Download
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