title: Enhanced osteoclast development in collagen-induced arthritis in interferon-gamma receptor knock-out mice as related to increased splenic CD11b+ myelopoiesis.
abstract: Collagen-induced arthritis (CIA) in mice is accompanied by splenomegaly due to the selective expansion of immature CD11b+ myeloblasts. Both disease manifestations are more pronounced in interferon-gamma receptor knock-out (IFN-gammaR KO) mice. We have taken advantage of this difference to test the hypothesis that the expanding CD11b+ splenic cell population constitutes a source from which osteoclast precursors are recruited to the joint synovia. We found larger numbers of osteoclasts and more severe bone destruction in joints of IFN-gammaR KO mice than in joints of wild-type mice. Osteoclast-like multinucleated cells appeared in splenocyte cultures established in the presence of macrophage colony-stimulating factor (M-CSF) and stimulated with the osteoclast-differentiating factor receptor activator of NF-kappaB ligand (RANKL) or with tumour necrosis factor-alpha (TNF-alpha). Significantly larger numbers of such cells could be generated from splenocytes of IFN-gammaR KO mice than from those of wild-type mice. This was not accompanied, as might have been expected, by increased concentrations of the intracellular adaptor protein TRAF6, known to be involved in signalling of RANKL- and TNF-alpha-induced osteoclast formation. Splenocyte cultures of IFN-gammaR KO mice also produced more TNF-alpha and more RANKL than those of wild-type mice. Finally, splenocytes isolated from immunised IFN-gammaR KO mice contained comparatively low levels of pro-interleukin-1beta (pro-IL-1beta) and pro-caspase-1, indicating more extensive conversion of pro-IL-1beta into secreted active IL-1beta. These observations provide evidence that all conditions are fulfilled for the expanding CD11b+ splenocytes to act as a source of osteoclasts and to be indirectly responsible for bone destruction in CIA. They also provide a plausible explanation for the higher susceptibility of IFN-gammaR KO mice to CIA.
authors.affiliation: Laboratory of Immunobiology, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: De Klerck
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carpentier
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Lories
authors.forename: Yvette
authors.initials: Y
authors.lastname: Habraken
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Alfons
authors.initials: A
authors.lastname: Billiau
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D004789:Enzyme Activation; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D007596:Joints / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D038042:Myelopoiesis / Q000502:physiology*; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017471:Receptors, Interferon / Q000172:deficiency*; D013154:Spleen / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D039481:CD11b Antigen; D002352:Carrier Proteins; D020169:Caspases; D024043:Collagen Type II; D007371:Interferon-gamma; D007375:Interleukin-1; D016173:Macrophage Colony-Stimulating Factor; D008562:Membrane Glycoproteins; D011498:Protein Precursors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017471:Receptors, Interferon; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C043830:interleukin 1 precursor