Abstract
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 (Δψm) 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.
Highlights
Bone marrow mesenchymal stromal cells (BMSCs) are among the most promising seed cells used in tissue engineering approaches and whose potential for the treatment of different conditions [1], especially bone diseases, has been widely explored [2]
BMSCs were incubated with different concentrations of DEXA for different time periods to evaluate which conditions were more efficient for inducing BMSC apoptosis
This study demonstrates for the first time the protective effect of artemisinin on primary cultured rat BMSCs against glucocorticoid-induced cellular damage via activation of extracellular-signal-regulated kinase 1/2 (ERK1/2)-cAMP response element binding protein (CREB) signaling pathway
Summary
Bone marrow mesenchymal stromal cells (BMSCs) are among the most promising seed cells used in tissue engineering approaches and whose potential for the treatment of different conditions [1], especially bone diseases, has been widely explored [2]. Osteoporosis (OP) is a common and very serious systemic bone metabolic disease that can be due to congenital factors (idiopathic OP) or induced by the decline of estrogen levels in menopausal women, by certain diseases, such as diabetes, or certain therapies, such as the long-term use of high concentrations of glucocorticoids. The mechanism of GIOP is related to an imbalance in the bone remodelling function, which involves the bone-forming osteoblasts (OB) and the bone-resorbing osteoclasts (OC) [14]. Extracellular matrix proteins are expressed and secreted by osteoblasts, resulting in the formation of nonmineralized bone matrix and osteoid. The osteoid proteins crosslink during the matrix maturation stage, forming a stronger and more stable structure. The osteoblasts are embedded in the bone as osteocytes and become bone-lining cells or undergo apoptosis [15, 16]
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