NF-κB p50 and p52 Expression Is Not Required for RANK-Expressing Osteoclast Progenitor Formation but Is Essential for RANK- and Cytokine-Mediated Osteoclastogenesis
Abstract
Expression of RANKL by stromal cells and of RANK and both NF-κB p50 and p52 by osteoclast precursors is essential for osteoclast formation. To examine further the role of RANKL, RANK, and NF-κB signaling in this process, we used NF-κB p50−/−;p52−/− double knockout (dKO) and wild-type (WT) mice. Osteoclasts formed in cocultures of WT osteoblasts with splenocytes from WT mice but not from dKO mice, a finding unchanged by addition of RANKL and macrophage colony-stimulating factor (M-CSF). NF-κB dKO splenocytes formed more colony-forming unit granulocyte macrophage (CFU-GM) colonies than WT cells, but no osteoclasts were formed from dKO CFU-GM colonies. RANKL increased the number of CFU-GM colonies twofold in WT cultures but not in dKO cultures. Fluorescence-activated cell sorting (FACS) analysis of splenocytes from NF-κB dKO mice revealed a two-to threefold increase in the percentage of CD11b (Mac-1) and RANK double-positive cells compared with WT controls. Treatment of NF-κB dKO splenocytes with interleukin (IL)-1, TNF-α, M-CSF, GM-CSF, and IL-6 plus soluble IL-6 receptor did not rescue the osteoclast defect. No increase in apoptosis was observed in cells of the osteoclast lineage in NF-κB dKO or p50−/−;p52+/− (3/4KO) mice. Thus, NF-κB p50 and p52 expression is not required for formation of RANK-expressing osteoclast progenitors but is essential for RANK-expressing osteoclast precursors to differentiate into TRAP+ osteoclasts in response to RANKL and other osteoclastogenic cytokines.
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Mice lacking both NF-κB 1 and 2 display severe osteopetrosis due to accumulation of osteoclast precursors.
“Mice lacking both NF-κB 1 and 2 display, among other features, severe osteopetrosis165 due to an accumulation of osteoclast precursors.166”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [166]
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Osteoclast differentiation and activation
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Self-citation
- Authors
- Xing, L., Bushnell, T. P., Carlson, L., Tai, Z., Tondravi, M., Siebenlist, U., Young, F., & Boyce, B. F.
- Affiliations
- University of Rochester Medicine (US)
- National Institutes of Health (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Corresponding author
- Boyce, Brendan F.
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-07-01
- Volume
- 17
- Issue
- 7
- Pages
- 1200-1210
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2163256279
- Cited by
- 165
- References
- 54
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 8 · 2014: 6 · 2013: 5 · 2012: 8
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 43510, R01AR043510)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- NF-κB p50, RANK, RANKL, osteoclastogenesis, osteoclast precursors, macrophage colony-stimulating factor, interleukin-1, TNF-α, GM-CSF, interleukin-6, CD11b, TRAP-positive osteoclasts, NF-κB signaling
- MeSH terms
- Animals, Antioxidants, Bone Marrow Cells, Carrier Proteins, Cell Differentiation, Cells, Cultured, Glycoproteins, Interleukin-1, Leupeptins, Membrane Glycoproteins, Osteoclasts, Proline, Spleen, Stem Cells, Thiocarbamates, Tosylphenylalanyl Chloromethyl Ketone, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Macrophage Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, NF-kappa B, Stromal Cells, Apoptosis, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Receptors, Interleukin-6, Mice, NF-kappa B p50 Subunit, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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