GADD45β-I attenuates oxidative stress and apoptosis via Sirt3-mediated inhibition of ER stress in osteoarthritis chondrocytes

Osteoarthritis (OA) is one of the most characterized joint diseases associated with chondrocyte apoptosis. JNK plays an important role in apoptosis in many pathological conditions, but systemic inhibition of JNK was shown to result in detrimental side effects. MAPK kinase 7 (MKK7) is a direct upstream kinase that regulates JNK and has been shown to activate JNK specifically under toxic conditions. In this study, we investigated the effect of GADD45β-I, a cell-permeable inhibitor targeted for MKK7, on IL-1β-induced cytotoxicity in rat chondrocytes. The results showed that IL-1β exposure resulted in toxicity in a dose-dependent manner, which was nullified by endoplasmic reticulum (ER) stress inhibitors. GADD45β-I significantly preserved cell survival, inhibited oxidative injury and reduced apoptosis after IL-1β treatment. ER stress in chondrocytes was attenuated by GADD45β-I, as evidenced by reduced levels of GRP78 and CHOP, as well as decreased caspase-12 cleavage. In addition, GADD45β-I increased the enzymatic activities of mitochondrial antioxidant enzymes, including IDH2, GSH-Px and SOD2. GADD45β-I significantly upregulated the expression of Sirt3 and attenuated IL-1β-induced acetylation of SOD2. Furthermore, GADD45β-I-induced inhibition of ER stress and protection in chondrocytes were partially reversed by knockdown of Sirt3. In conclusion, our data indicated that GADD45β-I protected chondrocytes against IL-1β through Sirt3-mediated inhibition of ER stress. Targeting MKK7 might be an ideal therapeutic strategy for reducing chondrocyte apoptosis in OA.