Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFκB
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Cytokines macrophage colony stimulating factor (M-CSF) and the receptor activator of NFkappaB 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 > or =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/NFkappaB 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-11Ralpha2, IL-6/11R gp130, IFNgammaR) 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 alpha1A-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.
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M-CSF ligation initiates expression of several cytokines and receptors and factors involved in the cell's response to RANKL ligation.
“M-CSF ligation also initiates the expression of several cytokines and their receptors including interleukin (IL)-1α, IL-18, interferon (IFN)-β, IL-11Rα2, IL-6/11R gp130, and IFN-γ-R; also expressed are factors involved in the cell’s response to RANKL ligation, including tumor necrosis factor receptor-associated factor 2A (TRAF2A), phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein Kin”
From Osteoclasts and Microgravity (2020) · cites this paper as [19]
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- Authors
- Cappellen, D., Luong-Nguyen, N.-H., Bongiovanni, S., Grenet, O., Wanke, C., & Šuša, M.
- Affiliations
- Novartis (Switzerland) (CH)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 277
- Issue
- 24
- Pages
- 21971-21982
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2004190331
- Cited by
- 184
- References
- 59
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 8 · 2017: 9 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 9
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- osteoclastogenesis, macrophage colony-stimulating factor, RANKL, RANK, NF-κB signaling, transcriptional programs, gene expression profiling, interleukins, interferon, interleukin-1, interleukin-6, interleukin-11, RANTES, insulin-like growth factor I, histamine, alpha1A-adrenergic receptor, PI3-kinase, MEKK3, RIPK1
- MeSH terms
- Animals, Carrier Proteins, Cell Differentiation, Cells, Cultured, Ligands, Membrane Glycoproteins, Osteoclasts, Phenotype, Protein Binding, RNA, Time Factors, Transcription, Genetic, Up-Regulation, Macrophage Colony-Stimulating Factor, NF-kappa B, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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