Glucocorticoid-Induced Autophagy Protects Osteocytes Against Oxidative Stress Through Activation of MAPK/ERK Signaling

Autophagy confers protective or detrimental effects on cells depending on the cellular context. We showed here that oxidative stress-induced cell death in osteocytic MLO-Y4 cells coincided with decreased autophagy. Decreased autophagy was also observed in osteocytes of superoxide dismutase 1- (SOD1-) deficient mice. Oxidative stress-induced osteocyte death was exacerbated by an autophagy inhibitor, chloroquine, suggesting a protective function of basal autophagy levels against oxidative stress-induced cell death. Pretreatment with dexamethasone reduced the susceptibility of osteocytes to oxidative stress-induced cell death and conferred protection against TNFα/cycloheximide-induced cell death. Inhibition of MAPK/ERK attenuated the formation of autophagosome, leading to increased osteocyte cell death. Taken together, our results suggest that autophagy, induced by moderate levels of glucocorticoids, leads to the preconditioning of osteocytes and conveys a novel cell-protective function against cell death induced by oxidative stress and other insults.