title: 8-Isoprostaglandin E2 enhances receptor-activated NFkappa B ligand (RANKL)-dependent osteoclastic potential of marrow hematopoietic precursors via the cAMP pathway.
abstract: Lipid oxidation products promote atherosclerosis and may also affect osteoporosis. We showed previously that oxidized lipids including 8-isoprostaglandin E2 (isoPGE2) inhibit osteoblastic differentiation of preosteoblasts. Since osteoporosis is mediated both by decreased osteoblastic bone formation and by increased osteoclastic bone resorption, we assessed whether oxidized lipids regulate the osteoclastic potential of marrow hematopoietic cells. Treatment of marrow-derived preosteoclasts with isoPGE2 enhanced osteoclastic differentiation as evidenced by increased tartrate-resistant acid phosphatase (TRAP) activity and multinucleation, which were inhibited by calcitonin, and increased numbers of resorption pits. The enhanced osteoclastic differentiation by isoPGE2 was observed whether preosteoclasts were in coculture with stromal cells or in monoculture in the presence of receptor-activated NFkappaB ligand (RANKL) and macrophage colony-stimulating factor. Receptor antagonist studies suggest that isoPGE2 effects were mediated by prostaglandin receptor subtypes EP2/DP on preosteoclasts and subtype EP1 and thromboxane receptors on stromal/osteoblast cells. The enhanced TRAP activity was also inhibited by cAMP-dependent protein kinase inhibitors, and isoPGE2 elevated intracellular cAMP levels of preosteoclast monocultures. Other oxidized lipids also enhanced the TRAP activity of preosteoclast monocultures. These data suggest that isoPGE2 enhances osteoclastic differentiation of marrow preosteoclasts and that this regulation occurs via the cAMP-dependent protein kinase pathway.
authors.affiliation: Department of Medicine, School of Medicine, UCLA, Los Angeles, California 90095, USA. ytintut@ucla.edu
authors.forename: Yin
authors.initials: Y
authors.lastname: Tintut
authors.forename: Farhad
authors.initials: F
authors.lastname: Parhami
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsingotjidou
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tetradis
authors.forename: Mary
authors.initials: M
authors.lastname: Territo
authors.forename: Linda L
authors.initials: LL
authors.lastname: Demer
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells; D002116:Calcitonin / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology*; D028421:Isoprostanes / Q000494:pharmacology*; D050356:Lipid Metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008858:Microscopy, Phase-Contrast; D010010:Osteoclasts / Q000378:metabolism*; D010024:Osteoporosis / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000199:Actins; D002352:Carrier Proteins; D028421:Isoprostanes; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014662:Vasoconstrictor Agents; D002116:Calcitonin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D010100:Oxygen; C011987:8-isoprostaglandin E2