title: Transforming growth factor-beta induces expression of receptor activator of NF-kappa B ligand in vascular endothelial cells derived from bone.
abstract: Vascular endothelial cells in bone are thought to have significant roles on pathological bone resorption such as bone metastasis and hypercalcemia because this resorption is often seen where blood vessels are abundant. However, the detailed mechanisms have not yet been elucidated. Here, we focused on transforming growth factor-beta (TGF-beta) and studied its effects on vascular endothelial cells because TGF-beta is abundantly stored in bone matrix and is released and activated during bone resorption. We found that TGF-beta up-regulated the expression of receptor activator of NF-kappa B ligand (RANKL) mRNA and protein in bone marrow-derived endothelial cells and in primary vascular endothelial cells but not in osteoblasts. Further analysis revealed that TGF-beta promoted phosphorylation of cAMP response element-binding protein and p38. Protein kinase A inhibitor KT5720 and p38 inhibitor SB203580 significantly reduced the TGF-beta-induced RANKL expression. Moreover, we found two CRE-like domains in murine RANKL promoter region that were critical for TGF-beta-dependent RANKL expression. Therefore, protein kinase A and p38 signaling pathways are involved in TGF-beta-induced RANKL expression by stimulating transcription factors that bind to the CRE-like domains. Our findings indicate that TGF-beta stimulates osteoclastogenesis by promoting RANKL expression in endothelial cells under pathological conditions.
authors: Institute of Molecular and Cellular Biosciences, the University of Tokyo, Tokyo 113-0032, Japan.
authors: Atsushi
authors: A
authors: Ishida
authors: Naoya
authors: N
authors: Fujita
authors: Riko
authors: R
authors: Kitazawa
authors: Takashi
authors: T
authors: Tsuruo
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002227:Carbazoles; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D015232:Dinoprostone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002227:Carbazoles; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011725:Pyridines; D011758:Pyrroles; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D016212:Transforming Growth Factor beta; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580