Open Access Research article

Enhanced osteoclast development in collagen-induced arthritis in interferon-γ receptor knock-out mice as related to increased splenic CD11b+ myelopoiesis

Bert De Klerck1, Isabelle Carpentier2, Rik J Lories3, Yvette Habraken4, Jacques Piette4, Geert Carmeliet5, Rudi Beyaert2, Alfons Billiau1 and Patrick Matthys1*

Author Affiliations

1 Laboratory of Immunobiology, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium

2 Department of Molecular Biomedical Research, Ghent University – VIB, Ghent, Belgium

3 Laboratory for Skeletal Development and Joint Disorders, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium

4 Laboratory of Virology and Immunology, Institute of Pathology, University of Liège, Liège, Belgium

5 Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium

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Arthritis Res Ther 2004, 6:R220-R231  doi:10.1186/ar1167

Published: 12 March 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