Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation

Advanced oxidation protein products (AOPPs) are recognized as novel markers of oxidative stress and contribute to various medical conditions, which are associated with secondary osteoporosis. However, little is currently known regarding the role of AOPPs in the development of secondary osteoporosis. As the commander cells of bone remodeling, osteocytes are involved in the pathogenesis of osteoporosis. The present study aimed to determine the cytotoxic mechanisms of AOPPs on osteocytic MLO-Y4 cells. The results demonstrated that treatment with AOPPs significantly triggered apoptosis of MLO-Y4 cells, in a dose- and time-dependent manner. Furthermore, exposure to AOPPs induced phosphorylation of c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK). Conversely, N-acetylcysteine inhibited the activation of JNK and p38 MAPK, thus suggesting that the AOPPs-induced activation of JNK/p38 MAPK is reactive oxygen species (ROS)-dependent. In addition, SB203580 and SP600125 suppressed apoptosis, but did not affect ROS production, following AOPPs treatment. Notably, AOPPs also induced a significant upregulation in the expression levels of sclerostin and receptor activator of nuclear factor kappa-B ligand (RANKL) in a JNK/p38 MAPK-dependent manner. These findings provide novel insights into the molecular mechanisms underlying AOPPs-mediated cell death, and suggest that modulation of apoptotic pathways via the MAPK signaling cascade may be considered a therapeutic strategy for the prevention and treatment of secondary osteoporosis.