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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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Xu, W., Yang, Y., Li, N., & Hua, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914484 · Cited by 38
“…receptor of nuclear factor For example, TNF-α mediates increased receptor activator of nuclear factor kappa-B ligand (RANKL) expression in macrophages, thereby stimulating osteoclastogenesis [18]. kappa-B ligand (RANKL) expression in macrophages, thereby stimulating osteoclastogenesis [18].”
BackgroundTseng, H.-C., Kanayama, K., Kaur, K., Park, S., Park, S., Kozłowska, A. K., Sun, S., McKenna, C. E., Nishimura, I., & Jewett, A. (2015) · Oncotarget · doi:10.18632/oncotarget.4755 · Cited by 92
“TNF-α, another key cytokine produced by NK cells, can increase RANKL expression and RANKL dependent osteoclastogenesis [9–11].”
Aryl Hydrocarbon Receptors in Osteoclast Lineage Cells Are a Negative Regulator of Bone Mass
Yu, T., Pang, W.-J., & Yang, G.-S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0117112 · Cited by 34
“When these cytokines stimulate their receptors, c-fms and RANK, respectively, transcription factors such as the cellular oncogene fos (c-Fos) [28], nuclear factor kappa B (NF-kB) [29], and NFATc1 [30] in osteoclast precursors are activated, and osteoclast differentiation is induced by the induction of osteoclastic gen…”
Bone Effects of Biologic Drugs in Rheumatoid Arthritis
Corrado, A., Neve, A., Maruotti, N., & Cantatore, F. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/945945 · Cited by 39
“…and activity both directly, in the presence of minimal concentration of RANKL or even in the absence of RANKL signalling [15, 16] and indirectly by increasing the expression of osteoclast activators (M-CSF and RANKL) in several cells such as osteoblasts and cells of immune system [17–19].”
BackgroundHoloshitz, J., Liu, Y., Fu, J., Joseph, J., Ling, S., Colletta, A., Sharma, P., Begun, D. L., Goldstein, S. A., & Taichman, R. S. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202150 · Cited by 34
“Both IL-6 and TNF-a enhance osteoclastogenesis, and their levels are substantially elevated in the synovial fluid of RA patients (36, 37).”
BackgroundObitsu, S., Ahmed, N., Nishitsuji, H., Hasegawa, A., Nakahama, K., Morita, I., Nishigaki, K., Hayashi, T., Masuda, T., & Kannagi, M. (2009) · Archives of Virology · doi:10.1007/s00705-009-0472-z · Cited by 41
“Inflammatory cytokines such as TNF-a also promote osteoclastogenesis in the presence of RANKL [11, 12] .”
BackgroundLymphocyte-derived cytokines in inflammatory arthritis
Horwood, N. (2008) · Autoimmunity · doi:10.1080/08916930701694766 · Cited by 39
“However, the expression of RANKL is essential for TNF to promote osteoclastogenesis as demonstrated using RANKL deficient mice [22].”
BackgroundOsteoclast differentiation and bone resorption in multicentric reticulohistiocytosis.
Adamopoulos, I., Wordsworth, P., Edwards, J., Ferguson, D., & Athanasou, N. (2006) · Human Pathology · doi:10.1016/j.humpath.2006.04.007 · Cited by 39
“TNFa is known to induce RANKL expression by bone stromal cells and to induce osteoclast formation by direct stimulation of macrophages exposed to permissive levels of RANKL [30,31].”
BackgroundSubramanian, S., Tovey, M., Afentoulis, M., Krogstad, A. P., Vandenbark, A., & Offner, H. (2005) · Clinical Immunology · doi:10.1016/j.clim.2005.01.006 · Cited by 39
T-cell involvement in osteoclast biology: implications for rheumatoid bone erosion
O’Gradaigh, D., & Compston, J. E. (2003) · Rheumatology · doi:10.1093/rheumatology/keg447 · Cited by 38
A Rat Model for Testing Pharmacologic Treatments of Pressure-Related Bone Loss
Åstrand, J., Skripitz, R., Skoglund, B., & Aspenberg, P. (2003) · Clinical Orthopaedics and Related Research · doi:10.1097/01.blo.0000052938.71325.46 · Cited by 39
Interleukin-9 Facilitates Osteoclastogenesis in Rheumatoid Arthritis
Kar, S., Gupta, R., Malhotra, R., Sharma, V., Farooque, K., Kumar, V. L., Chakraborty, S., & Mitra, D. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910397 · Cited by 41
“TNF-α is a potent osteoclastogenic cytokine as it not only enhances the RANKLinduced osteoclastogenesis but can mediate the process of osteoclastogenesis in a RANKLindependent manner [14].”
BackgroundLiu, Q., Zhao, J., Tan, R. X., Zhou, H., Lin, Z., Zheng, M., Romas, E., Xu, J., & Sims, N. A. (2014) · Scandinavian Journal of Rheumatology · doi:10.3109/03009742.2014.938113 · Cited by 35
Saikosaponin a inhibits RANKL-induced osteoclastogenesis by suppressing NF-κB and MAPK pathways.
Zhou, C., Liu, W., He, W., Wang, H., Chen, Q.-Q., & Song, H.-P. (2015) · International Immunopharmacology · doi:10.1016/j.intimp.2015.01.010 · Cited by 38
Critical Role of MKP-1 in Lipopolysaccharide-Induced Osteoclast Formation through CXCL1 and CXCL2
Valerio, M., Herbert, B., Basilakos, D. S., Browne, C., Yu, H.-G., & Kirkwood, K. (2014) · Cytokine · doi:10.1016/j.cyto.2014.08.007 · Cited by 38
“In this mechanism, TNF (and LPS) specifically activate NF-κB and JNK-dependent c-Fos (a subunit of AP-1) contributing to OC formation [30].”
BackgroundTNFα inhibits the development of osteoclasts through osteoblast-derived GM-CSF
Atanga, E., Dolder, S., Dauwalder, T., Wetterwald, A., & Hofstetter, W. (2011) · Bone · doi:10.1016/j.bone.2011.08.003 · Cited by 37
“The cytokine has been reported to support differentiation and activation of osteoclasts [31–34] while inhibiting the activity of osteoblast lineage cells, thus causing bone loss [35].”
BackgroundJules, J., Shi, Z., Liu, J., Xu, D., Wang, S., & Feng, X. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.149484 · Cited by 41
Cytoskeletal dysfunction dominates in DAP12-deficient osteoclasts
Zou, W., Zhu, T., Craft, C. S., Broekelmann, T. J., Mecham, R. P., & Teitelbaum, S. L. (2010) · Journal of Cell Science · doi:10.1242/jcs.069872 · Cited by 33
“Glutathione S-transferase (GST)-RANKL was expressed in our laboratory as described (Lam et al., 2000).”
MethodSelf-citationSD0006: A Potent, Selective and Orally Available Inhibitor of p38 Kinase
Burnette, B., Selness, S., Devraj, R., Jungbluth, G., Kurumbail, R., Stillwell, L., Anderson, G., Mnich, S., Hirsch, J., Compton, R., et al. (2009) · Pharmacology · doi:10.1159/000227286 · Cited by 38
“[J. Monahan, unpubl. obs.]. SD0006 was found to inhibit the transcription of several inflammatory mediators to prevent joint swelling and bone destruction and to preserve bone density.Because TNFα signaling modulates the expression of many genes induced by SCW, and has been reported to stimulate osteoclastogenesis in…”
BackgroundExpression of tumour necrosis factor-alpha in the rat dental follicle.
Wise, G. E., & Yao, S. (2003) · Archives of Oral Biology · doi:10.1016/s0003-9969(02)00153-x · Cited by 38
Chinthamani, S., Settem, R. P., Honma, K., Kay, J., & Sharma, A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0173394 · Cited by 37
RANKL-Independent Osteoclastogenesis: A Long-Standing Controversy
Tanaka, S. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3092 · Cited by 39
“Because the involvement of stromal cells is not negligible, as Tsukasaki and colleagues((1)) and previous studies reported,((23,28,29)) it is difficult to propose RANKLindependent osteoclastogenesis without the validation in RANKL-deficient or RANK-deficient conditions.”
BackgroundSSRIs, bone mineral density, and risk of fractures — a review
Schwan, S., & Hallberg, P. (2009) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2009.05.001 · Cited by 39
“IL-6 and TNF-α have been implicated in bone resorption attributable to their activation of osteoclastic cells (Cizza et al., 2001; Dentino et al., 1999; Hofbauer et al., 2000; Lam et al., 2000).”
BackgroundClassification criteria for rheumatoid arthritis--time to abandon rheumatoid factor?
Symmons, D. (2007) · Rheumatology · doi:10.1093/rheumatology/kel418 · Cited by 37
The role of osteoprotegerin in arthritis.
Schett, G. A., Redlich, K., & Smolen, J. S. (2003) · Arthritis Research · doi:10.1186/ar990 · Cited by 30
The burden of rheumatoid arthritis and access to treatment: a medical overview
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“may be of particular importance in governing the severity of the destructive response in RA, bone destruction is primarily mediated by activation of osteoclasts via the RANKL-RANK-receptor system [28-31].”
BackgroundNeuropathy and the vascular-bone axis in diabetes: lessons from Charcot osteoarthropathy
Petrova, N. L., & Shanahan, C. M. (2013) · Osteoporosis International · doi:10.1007/s00198-013-2511-6 · Cited by 31
Wongdee, K., Tulalamba, W., Thongbunchoo, J., Krishnamra, N., & Charoenphandhu, N. (2010) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-010-0674-4 · Cited by 39
“Previous studies have provided corroborative evidence that the TNF-ainduced osteoclast differentiation in vitro was augmented in the presence of RANKL [ 37 , 39], and the RANKLprimed osteoclasts did exist in ample number in maternal bone [7].”
ResultNovel targets in bone and cartilage
Beyer, C., & Schett, G. A. (2010) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2010.03.001 · Cited by 33
Zhu, H., Jiang, X.-X., Guo, Z.-K., Li, H., Su, Y.-F., Yao, H., Wang, X.-Y., Li, X.-S., Wu, Y., Liu, Y.-L., et al. (2009) · Stem Cells and Development · doi:10.1089/scd.2009.0021 · Cited by 36
Seo, S. W., Lee, D., Minematsu, H., Kim, A. D., Shin, M., Cho, S. K.-W., Kim, D. W., Yang, J., & Lee, F. Y. (2009) · Bone · doi:10.1016/j.bone.2009.10.032 · Cited by 37
Circulating RANKL is inversely related to RANKL mRNA levels in bone in osteoarthritic males
Findlay, D. M., Chehade, M. J., Tsangari, H., Neale, S. D., Hay, S. J., Hopwood, B., Pannach, S., O’Loughlin, P. D., & Fazzalari, N. L. (2008) · Arthritis Research & Therapy · doi:10.1186/ar2348 · Cited by 33
“vailing cytokine environment [8-10].”
Rheumatoid arthritis: inflammation and bone loss
Schett, G. A. (2006) · Wiener Medizinische Wochenschrift · doi:10.1007/s10354-005-0244-7 · Cited by 31
Functional roles of immune cells in osteoporosis
Qi, Z.-Q., Luo, J., Xiao, Z., & Yang, D. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1698283 · Cited by 35
“Neutrophils (NE) can also potentiate osteoclastogenesis, whereas mast cells (MC) release granules rich in osteoclastogenic mediators like interleukin (IL)-6 and tumor necrosis factor-a (TNF-a ) (5 – 7).”
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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