title: Interferon-gamma directly inhibits TRANCE-induced osteoclastogenesis.
abstract: The immune system has profound effects on bone remodeling. IFN-gamma, a major product of immune cells, potently inhibits bone resorption, but its mechanism of action is unknown. We found in cultures of stroma-free mononuclear precursors that IFN-gamma strongly suppresses TRANCE/RANKL-induced osteoclast formation in a dose-dependent manner. This direct effect on osteoclast progenitors was not due to stimulation of NO production by IFN-gamma, as the NOS inhibitors 1400W and L-NAME were unable to reverse the suppression. However, TGFbeta(1), which has opposing actions to IFN-gamma on diverse cellular functions, was able to antagonize the effect of IFN-gamma. This suggests that IFN-gamma prevents osteoclast formation by actively directing the differentiation of osteoclastic progenitors toward an alternative cytocidal lineage to the osteoclast.
authors.affiliation: Department of Histopathology, St. George's Hospital Medical School, London, SW17 ORE, United Kingdom.
authors.forename: S W
authors.initials: SW
authors.lastname: Fox
authors.forename: T J
authors.initials: TJ
authors.lastname: Chambers
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002417:Cattle; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D000578:Amidines; D001596:Benzylamines; D015415:Biomarkers; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009573:Nitrites; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C508961:Tgfb1 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester