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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 [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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Bone Density and Hyperlipidemia: The T-lymphocyte Connection
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“T-lymphocytes from the high-fat group, tested immediately ex vivo, show an increase in the message levels of several cytokines that have well-documented associations with inflammation and bone loss, including IL-6,((44)) TNF-a,((45)) and IL-1b.”
BackgroundDental Pulp and Periodontal Ligament Cells Support Osteoclastic Differentiation
Uchiyama, M., Nakamichi, Y., Nakamura, M., Kinugawa, S., Yamada, H., Udagawa, N., & Miyazawa, H. (2009) · Journal of dentistry research · doi:10.1177/0022034509340008 · Cited by 70
“monocytes and macrophages into osteoclasts in a RANKLRANK signal-independent manner (Kobayashi et al., 2000; Lam et al., 2000).”
BackgroundTsangari, H., Findlay, D. M., Kuliwaba, J. S., Atkins, G. J., & Fazzalari, N. L. (2004) · Bone · doi:10.1016/j.bone.2004.02.006 · Cited by 69
“The significant increase in the RANKL/OPG mRNA ratio in #NOF bone reported in this study may be important for potentiating RANKL-induced osteoclast formation [69].”
BackgroundHaynes, D. R. (2004) · Inflammation Research · doi:10.1007/s00011-004-1303-z · Cited by 66
“However, in vivo it is more likely to work in synergy with RANKL by making cells far more sensitive to low levels of RANKL [ 59 ].”
BackgroundHuang, W., O’Keefe, R. J., & Schwarz, E. M. (2002) · Arthritis Research & Therapy · doi:10.1186/ar612 · Cited by 67
“Convincing evidence has been generated indicating that the RANK–RANKL interaction is absolutely required for osteoclastogenesis [7]; in the absence of these molecules, osteoclastogenesis cannot occur [9].”
Chen, X., Zhang, Z., Hu, Y., Cui, J., Zhi, X., Li, X., Jiang, H., Wang, Y., Zhengrong, G., Qiu, Z., et al. (2020) · Aging and Disease · doi:10.14336/ad.2019.0613 · Cited by 81
“Drinking water containing 10% GOSLu (galacto-oligosaccharides derived from lactulose) prevents the development of colorectal cancer by significantly reducing intestinal populations of proinflammatory bacterial families, and significantly increasing beneficial populations [15].”
BackgroundOsteomicrobiology: The influence of gut microbiota on bone in health and disease
Jones, R. M., Mullé, J. G., & Pacifici, R. (2017) · Bone · doi:10.1016/j.bone.2017.04.009 · Cited by 79
Alves, C. H., Farrell, E., Vis, M., Colin, E. M., & Lubberts, E. (2015) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-015-8522-7 · Cited by 65
“Proinflammatory cytokines, as IL-1, IL-6, IL-17 and TNF-α, are able to stimulate osteoclast differentiation by expansion of the osteoclast precursor pool, up-regulation of RANKL expression in osteoblasts and/or in synovial fibroblasts and by synergism with RANKL itself, normally resulting in bone loss [26, 50, 51].”
BackgroundInflammation and Tooth Movement: The Role of Cytokines, Chemokines, and Growth Factors
Andrade, I., Taddei, S. R. A., & Souza, P. E. A. (2012) · Seminars in Orthodontics · doi:10.1053/j.sodo.2012.06.004 · Cited by 71
Liu, F., Zhu, Z., Mao, Y., Liu, M., Tang, T., & Qiu, S. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2008.12.018 · Cited by 71
“[51], who reported that TNF-a was unable to induce osteoclast precursors undergoing osteoclastogenesis in the absence of RANKL.”
BackgroundSmolen, J. S., van der Heijde, D. M. F. M., Aletaha, D., Xu, S., Han, J. S., Baker, D., & Clair, E. W. S. (2008) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.094128 · Cited by 63
The Role of Osteocytes in Inflammatory Bone Loss
Metzger, C. E., & Narayanan, S. A. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00285 · Cited by 82
Osteoclasts in the Inflammatory Arthritis: Implications for Pathologic Osteolysis
Jung, Y., Kang, Y. M., & Han, S. W. (2019) · Immune Network · doi:10.4110/in.2019.19.e2 · Cited by 73
“TNFα can dramatically enhance OC differentiation in the presence of low level of RANKL that is insufficient to induce OC formation, while TNFα alone without RANKL failed to induce the differentiation of OCs (25).”
BackgroundTemporal differential effects of proinflammatory cytokines on osteoclastogenesis
Moon, S.-J., Ahn, I. E., Jung, H., Yi, H., Kim, J., Kim, Y., Kwok, S.-K., Park, K.-S., Min, J., Park, S.-H., et al. (2013) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2013.1269 · Cited by 67
“Certain authors demonstrated that TNF-α, IL-1β and IL-6 induced osteoclast differentiation directly, in a RANKLindependent manner (18-20), whereas others showed that a permissive level of RANKL is necessary for TNF-α-induced osteoclastogenesis, thus concluding that TNF-α alone cannot induce osteoclast formation (21).”
BackgroundFinzel, S., Kraus, S., Schmidt, S., Hueber, A. J., Rech, J., Engelke, K., Englbrecht, M., & Schett, G. A. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2012-201580 · Cited by 64
Kyung, T.-W., Lee, J.-E., Shin, H., & Choi, H.-S. (2008) · Experimental and Molecular Medicine · doi:10.3858/emm.2008.40.1.52 · Cited by 67
“Although the association between RANKL and the direct or indirect effect of TNF-α on osteoclastogenesis is controversial (Azuma et al., 2000; Lam et al., 2000), RANKL does stimulate TNF-α expression in osteoclast precursor cells and homogenous populations of Raw264.”
BackgroundAZT Enhances Osteoclastogenesis and Bone Loss
Pan, G., Wu, X., Mckenna, M. A., Feng, X., Nagy, T., & Mcdonald, J. (2004) · AIDS Research and Human Retroviruses · doi:10.1089/0889222041217482 · Cited by 67
Baker, P., Howe, L., Garneau, J., & Roopenian, D. (2002) · FEMS Immunology & Medical Microbiology · doi:10.1111/j.1574-695x.2002.tb00601.x · Cited by 67
Zamri, F., & de Vries, T. D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.591365 · Cited by 66
“On the other hand TNF plays an inducing role in bone resorption by attributing to the receptor activator of Nf-kB Ligand (RANKL)-signaling pathway by directly activating osteoclast precursor cells (9, 10).”
BackgroundVeerappan, S., O'Morain, C., Daly, J., & Ryan, B. (2011) · Alimentary Pharmacology and Therapeutics · doi:10.1111/j.1365-2036.2011.04667.x · Cited by 66
Nozawa, K., Fujishiro, M., Kawasaki, M., Kaneko, H., Iwabuchi, K., Yanagida, M., Suzuki, F., Miyazawa, K., Takasaki, Y., Ogawa, H., et al. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2863 · Cited by 64
“as IL-1 and IL-6 [31,32].”
Oral mucosal dendritic cells and periodontitis: many sides of the same coin with new twists
Cutler, C. W., & Teng, Y.-T. A. (2007) · Periodontology 2000 · doi:10.1111/j.1600-0757.2007.00222.x · Cited by 63
“In contrast, another study shows that tumor necrosis factor-α up-regulates c-fms expression in osteoclast precursors and thus increases the number of circulating osteoclast precursors (80), suggesting that the effects of tumor necrosis factor-α signaling may be dependent on the developmental stage of the target cells.”
ResultGengenbacher, M., Sebald, H., Villiger, P., Hofstetter, W., & Seitz, M. (2007) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2007.076711 · Cited by 66
The “lively” cytokines network in β-Thalassemia Major-related osteoporosis
Morabito, N., Russo, G., Gaudio, A., Lasco, A., Catalano, A., Morini, E., Franchina, F., Maisano, D., Rosa, M. L. L., Plota, M., et al. (2007) · Bone · doi:10.1016/j.bone.2007.02.020 · Cited by 66
CpG oligonucleotides: novel regulators of osteoclast differentiation
Zou, W., Schwartz, H., Endres, S., Hartmann, G., & Bar-Shavit, Z. (2002) · The FASEB Journal · doi:10.1096/fj.01-0586com · Cited by 66
Potential mechanisms linking psychological stress to bone health
Ng, J.-S., & Chin, K.-Y. (2021) · International Journal of Medical Sciences · doi:10.7150/ijms.50680 · Cited by 66
“In particular, tumour necrosis alpha-α is a more potent osteoclastogenic factor than the other PICs since it can amplify RANKL signalling in osteoclasts [19, 46-48], thereby enhancing osteoclastogenesis and bone resorption.”
Kim, H.-R., Kim, K.-W., Kim, B.-M., Jung, H., Cho, M., & Lee, S.-H. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38286 · Cited by 65
“The cells produce RANKL in response to various stimuli, such as TNF , IL-1 , IL-6, IL-17, and prostaglandin E2, in RA (47).”
Backgroundc-Src Links a RANK/αvβ3 Integrin Complex to the Osteoclast Cytoskeleton
Izawa, T., Zou, W., Chappel, J. C., Ashley, J. W., Feng, X., & Teitelbaum, S. L. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00077-12 · Cited by 72
“our laboratory as described previously (14).”
Self-citationKrönke, G., Uderhardt, S., Kim, K., Stock, M., Scholtysek, C., Zaiss, M. M., Surmann‐Schmitt, C., Luther, J., Katzenbeisser, J., David, J., et al. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27496 · Cited by 67
Immature Osteoblast Lineage Cells Increase Osteoclastogenesis in Osteogenesis Imperfecta Murine
Li, H., Jiang, X., Delaney, J., Franceschetti, T., Bilić-Čurčić, I., Kalinowski, J., Lorenzo, J., Grčević, D., Rowe, D. W., & Kalajzić, I. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090704 · Cited by 65
“In addition to Rankl, other factors, specifically inflammatory cytokines such as TNF- and IL-1, can stimulate osteoclastogenesis.(23,24) This mechanism may be relevant in the OIM model because oim/oim mice can develop spontaneous fractures that, because of the tissue injury, are followed by inflammation and proinflamm…”
BackgroundResearch on the role and mechanism of the PI3K/Akt/mTOR signalling pathway in osteoporosis
Liu, C., Zhang, J., Ye, Z.-Y., Luo, J., Peng, B., & Wang, Z.-X. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1541714 · Cited by 64
Synovial Immunophenotype and Anti–Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients
Orr, C. K., Najm, A., Biniecka, M., McGarry, T., Ng, C. T., Young, F., Fearon, U., & Veale, D. J. (2017) · Arthritis & Rheumatology · doi:10.1002/art.40218 · Cited by 64
Fujii, T., Kitaura, H., Kimura, K., Hakami, Z. W., & Takano‐Yamamoto, T. (2012) · Bone · doi:10.1016/j.bone.2012.06.024 · Cited by 68
“showed that TNF-α does not induce osteoclastogenesis on its own; it does so by directly targeting macrophages within a stromal environment that express permissive levels of RANKL [32].”
BackgroundInfluential
Metadata
- 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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