CaMKⅡ mediates cadmium induced apoptosis in rat primary osteoblasts through MAPK activation and endoplasmic reticulum stress

Ca2+ is an important ion in various intracellular metabolic pathways. Endoplasmic reticulum (ER) is a major intracellular calcium store and ER calcium homeostasis plays a key part in the regulation of apoptosis. We have previously shown that Cadmium (Cd) induces apoptosis in osteoblasts (OBs), accompany by increased cytoplasmic calcium. As the role of calcium in OBs apoptosis induced by Cd has not been clarified we investigated the effects of Cd exposure in rat OBs on intracellular Ca2+, CaMKII phosphorylation, and the pathways implicated in inducing apoptosis. The results showed that cadmium(Cd) induced elevation of intracellular Ca2+ ([Ca2+]i) in OBs by the release of Ca2+ from ER and the inflow of Ca2+ from the extracellular matrix. Cd induced [Ca2+]i elevation and phosphorylation of CaMKII which might be involved in activation of MAPKs and participated in Cd-induced mitochondrial apoptosis through the alteration of the ratio of Bax/Bcl-2 expression. Meanwhile, CaMKII phosphorylation activated unfolded protein response (UPR) during cadmium treatment and could enable the ER apoptosis pathway through the activation of caspase-12. These results indicated that CaMKII plays an important role in Cd induced ER apoptosis and MAPK activation. Our data provide new insights into the mechanisms underlying apoptosis in OBs following Cd exposure. This provides a theoretical basis for future investigations into the clinical therapeutic application of CaMKⅡ inhibitors in osteoporosis induced by Cd exposure.