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Originally published In Press as doi:10.1074/jbc.M200434200 on March 28, 2002

J. Biol. Chem., Vol. 277, Issue 24, 21971-21982, June 14, 2002
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Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFkappa B*

David CappellenDagger , Ngoc-Hong Luong-NguyenDagger , Sandrine Bongiovanni§, Olivier Grenet§, Christoph Wanke§, and Mira SusaDagger

From the Dagger  Novartis Pharma Research, Arthritis and Bone Metabolism Therapeutic Area, § Novartis Pharma Development, Pharmacogenomics Area, CH-4002 Basel, Switzerland

Cytokines macrophage colony stimulating factor (M-CSF) and the receptor activator of NFkappa B ligand (RANKL) induce differentiation of bone marrow hematopoietic precursor cells into bone-resorbing osteoclasts without the requirement for stromal cells of mesenchymal origin. We used this recently described mouse cell system and oligonucleotide microarrays representing about 9,400 different genes to analyze gene expression in hematopoietic cells undergoing differentiation to osteoclasts. The ability of microarrays to detect the genes of interest was validated by showing expression and expected regulation of several osteoclast marker genes. In total 750 known transcripts were up-regulated by >= 2-fold, and 91% of them at an early time in culture, suggesting that almost the whole differentiation program is defined already in pre-osteoclasts. As expected, M-CSF alone induced the receptor for RANKL (RANK), but also, unexpectedly, other RANK/NFkappa B pathway components (TRAF2A, PI3-kinase, MEKK3, RIPK1), providing a molecular explanation for the synergy of M-CSF and RANKL. Furthermore, interleukins, interferons, and their receptors (IL-1alpha , IL-18, IFN-beta , IL-11Ralpha 2, IL-6/11R gp130, IFNgamma R) were induced by M-CSF. Although interleukins are thought to regulate osteoclasts via modulation of M-CSF and RANKL expression in stromal cells, we showed that a mix of IL-1, IL-6, and IL-11 directly increased the activity of osteoclasts by 8.5-fold. RANKL induced about 70 novel target genes, including chemokines and growth factors (RANTES (regulated on activation, normal T cell expressed and secreted), PDGFalpha , IGF1), histamine, and alpha 1A-adrenergic receptors, and three waves of distinct receptors, transcription factors, and signaling molecules. In conclusion, M-CSF induced genes necessary for a direct response to RANKL and interleukins, while RANKL directed a three-stage differentiation program and induced genes for interaction with osteoblasts and immune and nerve cells. Thus, global gene expression suggests a more dynamic role of osteoclasts in bone physiology than previously anticipated.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Novartis Pharma Research, Arthritis and Bone Metabolism Therapeutic Area, WKL-125.9.12, CH-4002 Basel, Switzerland. Tel.: 41-61-696-44-49; Fax: 41-61-696-38-49; E-mail: mira.susa_spring@pharma.novartis.com.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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