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Logo of arthrestherBioMed Centralbiomed central web sitesearchsubmit a manuscriptregisterthis articleArthritis Research & Therapy
 
Arthritis Res Ther. 2004; 6(3): R220–R231.
Published online Mar 12, 2004. doi:  10.1186/ar1167
PMCID: PMC416444
Enhanced osteoclast development in collagen-induced arthritis in interferon-γ receptor knock-out mice as related to increased splenic CD11b+ myelopoiesis
Bert De Klerck,1 Isabelle Carpentier,2 Rik J Lories,3 Yvette Habraken,4 Jacques Piette,4 Geert Carmeliet,5 Rudi Beyaert,2 Alfons Billiau,1 and Patrick Matthyscorresponding author1
1Laboratory of Immunobiology, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium
2Department of Molecular Biomedical Research, Ghent University – VIB, Ghent, Belgium
3Laboratory for Skeletal Development and Joint Disorders, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium
4Laboratory of Virology and Immunology, Institute of Pathology, University of Liège, Liège, Belgium
5Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
corresponding authorCorresponding author.
Patrick Matthys: patrick.matthys/at/rega.kuleuven.ac.be
Received December 12, 2003; Revisions requested January 9, 2004; Revised February 20, 2004; Accepted February 24, 2004.
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-γ receptor knock-out (IFN-γR 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-γR 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-κB ligand (RANKL) or with tumour necrosis factor-α (TNF-α). Significantly larger numbers of such cells could be generated from splenocytes of IFN-γR 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-α-induced osteoclast formation. Splenocyte cultures of IFN-γR KO mice also produced more TNF-α and more RANKL than those of wild-type mice. Finally, splenocytes isolated from immunised IFN-γR KO mice contained comparatively low levels of pro-interleukin-1β (pro-IL-1β) and pro-caspase-1, indicating more extensive conversion of pro-IL-1β into secreted active IL-1β. 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-γR KO mice to CIA.
Keywords: osteoclast differentiation factor, osteoprotegerin ligand, receptor activator of NF-κB ligand, tumour necrosis factor receptor-associated factor
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