TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand
Open accessAbstract
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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TNF-α induces osteoclastogenesis in RANKL- and M-CSF-positive hematopoietic cell precursors, with effects mediated by TNF-α receptors type 1 and type 2, the former being most effective in inducing differentiation of TRAP-positive multinucleated cells.
“TNF-α induces osteoclastogenesis in RANKL- and M-CSF-positive hematopoietic cell precursors [29,30], where its effects are mediated by TNF-α receptors type 1 (p55r) and type 2 (p75r), the former being the most effective in inducing the differentiation of TRAP-positive multinucleated cells [31].”
From Osteoclasts and Microgravity (2020) · cites this paper as [29]
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“found that TNFα alone failed to induce OC formation from a pure M-BMMφ, whereas it dramatically stimulated their differentiation in the presence of permissive levels of RANKL [90], suggesting a synergistic effect of TNFα and RANKL on OC differentiation, and an important role of TNFα in OC formation in vivo on the bone…”
BackgroundTransforming Growth Factor β Affects Osteoclast Differentiation via Direct and Indirect Actions
Quinn, J. M. W., Itoh, K., Udagawa, N., Häusler, K., Yasuda, H., Shima, N., Mizuno, A., Higashio, K., Takahashi, N., Suda, T., et al. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.10.1787 · Cited by 278 · see citing works
“(35) suggests that osteoclasto genic response to TNFa depends on prior exposure of cells to low levels of RANKL (including before extraction of cells from tissue of origin), which is difficult to assess or to control for.”
BackgroundToraldo, G., Roggia, C., Qian, W.-P., Pacifici, R., & Weitzmann, M. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0136772100 · Cited by 276 · see citing works
The IκB Function of NF-κB2 p100 Controls Stimulated Osteoclastogenesis
Novack, D., Yin, L., Hagen-Stapleton, A., Schreiber, R. D., Goeddel, D., Ross, F. P., & Teitelbaum, S. L. (2003) · Journal of Experimental Medicine · doi:10.1084/jem.20030116 · Cited by 275 · see citing works
Self-citationTakeshita, S., Namba, N., Zhao, J. J., Jiang, Y., Genant, H. K., Silva, M. J., Brodt, M. D., Helgason, C. D., Kalesnikoff, J., Rauh, M. J., et al. (2002) · Nature Medicine · doi:10.1038/nm752 · Cited by 250 · see citing works
“This observation suggests that M-CSF may stimulate not only signals mediating proliferation and/or survival, but in specific circumstances—as is the case for TNF-α (ref”
BackgroundSelf-citationWeitzmann, M., Roggia, C., Toraldo, G., Weitzmann, L., & Pacifici, R. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15687 · Cited by 271 · see citing works
Weitzmann, M. (2013) · Scientifica · doi:10.1155/2013/125705 · Cited by 270 · see citing works
“…of this interconnection of the immune and skeletal systems more than a decade ago has now spawned the emergence of a dedicated field of study, sometimes referred to as “osteoimmunology,” different aspects of which have been the subject of a number of excellent review articles including [14–23].”
BackgroundInhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo
Axmann, R., Böhm, C., Krönke, G., Zwerina, J., Smolen, J., & Schett, G. (2009) · Arthritis & Rheumatism · doi:10.1002/art.24781 · Cited by 263 · see citing works
Dankbar, B., Fennen, M., Brunert, D., Hayer, S., Frank, S., Wehmeyer, C., Beckmann, D., Paruzel, P., Bertrand, J., Redlich, K., et al. (2015) · Nature Medicine · doi:10.1038/nm.3917 · Cited by 262 · see citing works
Ruocco, M. G., Maeda, S., Park, J. M., Lawrence, T., Hsu, L.-C., Cao, Y., Schett, G., Wagner, E. F., & Karin, M. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20042081 · Cited by 252 · see citing works
“However, it remains controversial whether TNF promotes osteoclastogenesis independently of RANKL (10, 11).”
BackgroundInflammatory osteolysis: A conspiracy against bone
Mbalaviele, G., Novack, D. V., Schett, G., & Teitelbaum, S. L. (2017) · Journal of Clinical Investigation · doi:10.1172/jci93356 · Cited by 251 · see citing works
Self-citationOsteoclast precursors, RANKL/RANK, and immunology
Xing, L., Schwarz, E. M., & Boyce, B. F. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00336.x · Cited by 234 · see citing works
“One argument against RANKL-independent osteoclastogenesis is that OCPs must be primed by RANKL in vivo before TNF can induce them to differentiate into osteoclasts in vitro (77).”
BackgroundTNF-α Directly Enhances Osteocyte RANKL Expression and Promotes Osteoclast Formation
Marahleh, A., Kitaura, H., Ohori, F., Kishikawa, A., Ogawa, S., Shen, W.-R., Qi, J., Noguchi, T., Nara, Y., & Mizoguchi, I. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02925 · Cited by 243 · see citing works
Mechanisms and control of pathologic bone loss in periodontitis
Bartold, P. M., Cantley, M. D., & Haynes, D. R. (2010) · Periodontology 2000 · doi:10.1111/j.1600-0757.2010.00347.x · Cited by 252 · see citing works
“However, this finding has been challenged and RANKL is generally accepted as the essential ingredient for osteoclast formation (52).”
BackgroundTNF.ALPHA. and pathologic bone resorption
Boyce, B., Li, P., Yao, Z., Zhang, Q., Badell, I. R., Schwarz, E. M., O’Keefe, R. J., & Xing, L. (2005) · The Keio Journal of Medicine · doi:10.2302/kjm.54.127 · Cited by 260 · see citing works
Pathogenic Mechanisms and Host Interactions in Staphylococcus epidermidis Device-Related Infection
Bresco, M. S., Harris, L. G., Thompson, K., Stanić, B., Morgenstern, M., O’Mahony, L., Richards, R. G., & Moriarty, T. F. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01401 · Cited by 237 · see citing works
“Based on cytokines induced by S. epidermidis in the different studies (e.g., IL-6, IFN-γ, or IL-12), a Th1/Th17 polarization may be expected in such infections.”
BackgroundInfluentialMoriarty, T. F., Metsemakers, W., Morgenstern, M., Hofstee, M. I., Diaz, A. V., Cassat, J., Wildemann, B., Depypere, M., Schwarz, E., & Richards, R. G. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00396-0 · Cited by 224 · see citing works
Myeloma bone disease: Pathophysiology and management
Silbermann, R., & Roodman, G. (2013) · Journal of Bone Oncology · doi:10.1016/j.jbo.2013.04.001 · Cited by 223 · see citing works
Iqbal, J., Sun, L., Kumar, T., Blair, H., & Zaidi, M. (2006) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0606805103 · Cited by 222 · see citing works
Osteoclasts, rheumatoid arthritis, and osteoimmunology
Sato, K., & Takayanagi, H. (2006) · Current Opinion in Rheumatology · doi:10.1097/01.bor.0000231912.24740.a5 · Cited by 222 · see citing works
Kogianni, G., Mann, V., & Noble, B. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.080207 · Cited by 221 · see citing works
“TNF- has been shown to either cooperate with RANKL((35,36)) or to”
BackgroundLi, P., Schwarz, E. M., O'Keefe, R. J., Ma, L., Boyce, B. F., & Xing, L. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.0301233 · Cited by 220 · see citing works
“The activation of NF- B and AP-1 signaling pathways by TNF have been well documented in bone marrow–derived macrophages, which become enriched for CD11b cells after M-CSF treatment.((21,38)) These pathways regulate proliferation, differentiation, and survival in many cell types.”
BackgroundThe Effect of Inflammation on Bone
Epsley, S., Tadros, S., Farid, A., Kargilis, D., Mehta, S., & Rajapakse, C. S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.511799 · Cited by 242 · see citing works
- 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.
- Venue
- Journal of Clinical Investigation
- Published
- 2000-12-15
- Volume
- 106
- Issue
- 12
- Pages
- 1481-1488
- ISSN
- 0021-9738 (ISSN-L)
- 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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