RRC ID 73044
Author Ishida A, Fujita N, Kitazawa R, Tsuruo T.
Title Transforming growth factor-beta induces expression of receptor activator of NF-kappa B ligand in vascular endothelial cells derived from bone.
Journal J Biol Chem
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.
Volume 277(29)
Pages 26217-24
Published 2002-7-19
DOI 10.1074/jbc.M111093200
PII S0021-9258(19)66362-3
PMID 12011070
MeSH Animals Bone and Bones / cytology Bone and Bones / metabolism* Carbazoles* Carrier Proteins / biosynthesis* Carrier Proteins / genetics Cells, Cultured Cyclic AMP Response Element-Binding Protein / metabolism Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors Dinoprostone / metabolism Endothelium, Vascular / metabolism* Enzyme Inhibitors / pharmacology Humans Imidazoles / pharmacology Indoles / pharmacology Membrane Glycoproteins / biosynthesis* Membrane Glycoproteins / genetics Mice Mitogen-Activated Protein Kinases / metabolism NF-kappa B / metabolism* Osteoclasts / metabolism Phosphorylation Promoter Regions, Genetic Pyridines / pharmacology Pyrroles / pharmacology RANK Ligand RNA, Messenger / metabolism Receptor Activator of Nuclear Factor-kappa B Transforming Growth Factor beta / metabolism* p38 Mitogen-Activated Protein Kinases
IF 4.238
Human and Animal Cells ST2(RCB0224)