Cited by 1,440Bone Metabolism and DiseasesOsteomyelitis and Bone Disorders ResearchRheumatoid Arthritis Research and Therapies

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TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand

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Lam, Jonathan, Takeshita, Sunao, Barker, Jane E., Kanagawa, Osami, Ross, F. Patrick, Teitelbaum, Steven L.·2000·Journal of Clinical Investigation

DOI 10.1172/jci11176PMC PMC387259

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Abstract

While TNF-alpha is pivotal to the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction are unknown. We find that a pure population of murine osteoclast precursors fails to undergo osteoclastogenesis when treated with TNF-alpha alone. In contrast, the cytokine dramatically stimulates differentiation in macrophages primed by less than one percent of the amount of RANKL (ligand for the receptor activator of NF-kappaB) required to induce osteoclast formation. Mirroring their synergistic effects on osteoclast differentiation, TNF-alpha and RANKL markedly potentiate NF-kappaB and stress-activated protein kinase/c-Jun NH(2)-terminal kinase activity, two signaling pathways essential for osteoclastogenesis. In vivo administration of TNF-alpha prompts robust osteoclast formation in chimeric animals in which ss-galactosidase positive, TNF-responsive macrophages develop within a TNF-nonresponsive stromal environment. Thus, while TNF-alpha alone does not induce osteoclastogenesis, it does so both in vitro and in vivo by directly targeting macrophages within a stromal environment that expresses permissive levels of RANKL. Given the minuscule amount of RANKL sufficient to synergize with TNF-alpha to promote osteoclastogenesis, TNF-alpha appears to be a more convenient target in arresting inflammatory osteolysis.

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“TNFα alone does not increase the differentiation of osteoclast precursor cells (Kobayashi et al., 2000; Lam et al., 2000), but has been shown to act synergistically together with RANKL on osteoclastogenesis (Azuma et al., 2000; Lam et al., 2000; Fuller et al., 2002).”
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“A key mechanism by which TNFα promotes bone resorption is increasing the sensitivity of osteoclast precursors to RANKL activity (12, 13).”
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Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis*
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“…differentiation (e.g. IL-1b, TGF-b, TNF-a) might enhance this function by recruiting preosteoclasts and promoting osteoclast differentiation (Lam et al. 2000, Cheon et al. 2002, Wei et al. 2005, Kindle et al. 2006) and/ or by modulating RANKL and OPG levels (Hofbauer et al. 1999, Koenders…”
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Background

Authors: Lam, J., Takeshita, S., Barker, J. E., Kanagawa, O., Ross, F. P., & Teitelbaum, S. L.
Affiliations: Washington University in St. Louis (US)
Barnes-Jewish Hospital (US)
Corresponding author: Teitelbaum, Steven L.
ORCID: Kanagawa, Osami
Teitelbaum, Steven L.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2000-12-15
Volume: 106
Issue: 12
Pages: 1481-1488
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci11176
PMC: PMC387259
OpenAlex: W2132933661
Cited by: 1,440
References: 0
Citations by year: 2026: 45 · 2025: 63 · 2024: 48 · 2023: 53 · 2022: 60 · 2021: 72 · 2020: 57 · 2019: 61 · 2018: 59 · 2017: 75 · 2016: 61 · 2015: 56 · 2014: 49 · 2013: 64 · 2012: 58
FWCI: 11.22
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders: National Institutes of Health
National Institute of General Medical Sciences (T32GM007200)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK027726)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-32788, AR-07033, R01AR032788, R37AR046523, T32AR007033, R01AR046852, AR46523, R01AR046523)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords: TNF-α, osteoclastogenesis, RANK ligand, macrophages, osteoclast precursors, NF-κB signaling, JNK signaling, inflammatory osteolysis, bone destruction, chimeric mice, cytokine synergy
MeSH terms: Animals, Carrier Proteins, Cell Differentiation, Cells, Cultured, Drug Synergism, Enzyme Activation, Flow Cytometry, Histocytochemistry, Macrophages, Membrane Glycoproteins, Osteoclasts, Stem Cells, Tumor Necrosis Factor-alpha, Bone Marrow Transplantation, NF-kappa B, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B

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TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand

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