title: Exposure to receptor-activator of NFkappaB ligand renders pre-osteoclasts resistant to IFN-gamma by inducing terminal differentiation.
abstract: While it has been established that IFN-gamma is a strong activator of macrophages and a potent inhibitor of osteoclastogenesis in vitro, it is also known that this cytokine is produced in particular settings of inflammatory bone loss, such as infection and psoriatic arthritis. Because of the different kinetics between rapid IFN-gamma macrophage activation (<24 hours) and the slower receptor-activator of NFkappaB ligand (RANKL) osteoclast differentiation (7 days), we postulated that IFN-gamma would have different effects on early-stage and late-stage osteoclast precursors. In RAW264.7 cells and primary splenocyte cultures, pretreatment with RANKL rendered these cells resistant to maximally anti-osteoclastogenic doses of IFN-gamma. These cells were also resistant to IFN-gamma-induced nitric oxide production, morphological change, and surface upregulation of CD11b and receptor-activator of NFkappaB, suggesting that early exposure of osteoclast precursors to RANKL induces a broad resistance to the cellular effects of IFN-gamma. Changes in STAT1 activation did not correlate with this resistance, as IFN-gamma activated STAT1 equally in both early-stage and late-stage pre-osteoclasts. Furthermore, we failed to observe changes in TRAF6 expression following IFN-gamma treatment in pre-osteoclasts. Together these data support a model of inflammatory bone loss in which early exposure to RANKL can prime osteoclast precursors to form in the presence of high levels of IFN-gamma using mechanisms independent of the signal molecules STAT1 and TRAF6.
authors.affiliation: The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA. edward_schwarz@urmc.rochester.edu
authors.forename: Willis
authors.initials: W
authors.lastname: Huang
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D007371:Interferon-gamma