title: Sphingosine-1-phosphate protects against bisphosphonate‑induced HUVEC cell death via regulation of c-Jun‑N‑terminal kinase signaling.
abstract: Bisphosphonates (BPs) remain the most widely used and effective antiresorptive agents in the treatment of postmenopausal 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-1-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 S1P against BP-induced cell damage using human umbilical vein endothelial cells (HUVECs). HUVECs were treated with S1P for 1 h and then with BP including alendronate, zoledronate and risedronate. S1P protects HUVECs against BP-induced cell death and the protective effect was increased by S1P in a dose-dependent manner. S1P blocked BP-induced caspase-3 activation, nuclear factor-κB 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 S1P inhibits BP-induced endothelial cell death via regulation of JNK phosphorylation, and also suggests that S1P has the potential to be a therapeutic drug in various vascular diseases induced by BP.
authors: Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors: You-Jin
authors: YJ
authors: Lee
authors: Jae-Kyo
authors: JK
authors: Jeong
authors: Ju-Hee
authors: JH
authors: Lee
authors: Yang-Gyu
authors: YG
authors: Park
authors: Ji-Hong
authors: JH
authors: Moon
authors: Jae-Won
authors: JW
authors: Seol
authors: Christopher J
authors: CJ
authors: Jackson
authors: Sang-Youel
authors: SY
authors: Park
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004164:Diphosphonates; D008246:Lysophospholipids; D016328:NF-kappa B; D020011:Protective Agents; C060506:sphingosine 1-phosphate; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D013110:Sphingosine