Sphingosine-l-phosphate protects against bisphosphonate-induced HUVEC cell death via regulation of c-Jun-N-terminal kinase signaling

Bisphosphonates (BPs) remain the most widely used and effective antiresorptive agents in the treatment of post-menopausal osteoporosis. In particular, nitrogen-containing BPs (N-BPs) are more potent at inhibiting bone resorption in vivo than simple BPs, but they are associated with a number of side-effects including increased endothelial cell apoptosis in patients with multiple myeloma. Sphingosine-l-phosphate (S1P), a sphingolipid metabolite, plays important roles in the regulation of cell growth, differentiation and programmed cell death as a multifunctional bioactive lipid mediator. The aim of this study was to elucidate the protective effect and the possible mechanism of SIP against BP-induced cell damage using human umbilical vein endothelial cells (HUVECs). HUVECs were treated with SlP for 1 h and then with BP including alendronate, zoledronate and risedronate. SIP protects HUVECs against BP-induced cell death and the protective effect was increased by SIP in a dose-dependent manner. SlP blocked BP-induced caspase-3 activation, nuclear factor-kappa B activation, c-Jun-N-terminal kinase (JNK) phosphorylation and DNA fragmentation. The blocking of JNK phosphorylation inhibited BP-induced caspase activation and HUVEC cell death. The present study demonstrates that SIP inhibits BP-induced endothelial cell death via regulation of JNK phosphorylation, and also suggests that SlP has the potential to be a therapeutic drug in various vascular diseases induced by BR