Artemisinin Reverses Glucocorticoid-Induced Injury in Bone Marrow-Derived Mesenchymal Stem Cells through Regulation of ERK1/2-CREB Signaling Pathway

Glucocorticoids are the most common cause of secondary osteoporosis, which affects both women (pre- and postmenopausal) and men. In cases of prolonged treatment, glucocorticoids promote the loss and inactivation of the differentiational function of bone marrow mesenchymal stromal cells (BMSCs), risking the development of skeletal system diseases such as osteoporosis. This study reports for the first time the protective effect of the antimalarial artemisinin against glucocorticoid-induced insults on primary cultured rat BMSCs. At relatively low concentrations, artemisinin treatment improved BMSC survival by promoting a decline of reactive oxygen species (ROS) production that correlated with the decrease of caspase-3 activation, LDH release, mitochondrial membrane potential (Delta psi m) loss, and apoptosis induced by dexamethasone (DEXA). In addition, artemisinin improved the osteogenic differentiation of DEXA-damaged cells. DEXA inhibited extracellular-signal-regulated kinase 1/2 (ERK1/2) and cAMP response element binding protein (CREB) phosphorylation, and artemisinin treatment promoted their activation in a concentration-dependent manner. PD98059, the specific inhibitor of the ERK1/2 pathway, blocked ERK1/2 phosphorylation and artemisinin protection. Similarly, siCREB attenuated the protective effect of artemisinin, strongly suggesting the involvement of the ERK1/2-CREB pathway in the protective action of artemisinin against DEXA-induced damage in BMSCs. In addition, we found that the expression of antiapoptotic protein B-cell lymphoma 2 protein (BCL-2) was also upregulated by artemisinin. These studies demonstrate the therapeutic potential of artemisinin in the survival improvement of BMSCs exposed to glucocorticoid-induced apoptosis and suggest that artemisinin-mediated protection may occur via the activation of ERK1/2-CREB signaling pathway.