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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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Kong, Y.-Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., Morony, S., Capparelli, C., Li, J., Elliott, R., McCabe, S., et al. (1999) · Nature · doi:10.1038/46303 · Cited by 1,856
Li, J., Sarosi, I., Yan, X.-Q., Morony, S., Capparelli, C., Tan, H.-L., McCabe, S., Elliott, R., Scully, S., Van, G., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1566 · Cited by 1,119
Research works printed but not linked: 26
- Lannigan, 1993, J Laryngol Otol, 107, 12, 10.1017/S0022215100122005 · DOI
- Baroukh, 1991, J Periodontal Res, 26, 161, 10.1111/j.1600-0765.1991.tb01640.x · DOI
- Nair, 1996, Infect Immun, 64, 2371, 10.1128/IAI.64.7.2371-2380.1996 · DOI
- Bom-van Noorloos, 1990, J Clin Periodontol, 17, 409, 10.1111/j.1600-051X.1990.tb02338.x · DOI
- Birkedal-Hansen, 1993, J Periodontal Res, 28, 500, 10.1111/j.1600-0765.1993.tb02113.x · DOI
- Abu-Amer, 1997, J Clin Invest, 100, 1557, 10.1172/JCI119679 · DOI
- Abu-Amer, 1998, J Biol Chem, 273, 29417, 10.1074/jbc.273.45.29417 · DOI
- Teitelbaum, 2000, Science, 289, 1504, 10.1126/science.289.5484.1504 · DOI · Paper page
- Quinn, 2000, J Bone Miner Res, 15, 1459, 10.1359/jbmr.2000.15.8.1459 · DOI
- Ross, 2000, J Clin Invest, 105, 555, 10.1172/JCI9557 · DOI
- Kobayashi, 2000, J Exp Med, 191, 275, 10.1084/jem.191.2.275 · DOI
- Azuma, 2000, J Biol Chem, 275, 4858, 10.1074/jbc.275.7.4858 · DOI · Paper page
- McHugh, 2000, J Clin Invest, 105, 433, 10.1172/JCI8905 · DOI
- Sudo, 1995, Oncogene, 11, 2469
- Beutler, 1987, Lymphokines, 14, 203, 10.1016/B978-0-12-432014-7.50012-7 · DOI
- Ledgerwood, 1999, Lab Invest, 79, 1041
- Siwik, 2000, Circ Res, 86, 1259, 10.1161/01.RES.86.12.1259 · DOI
- Hofbauer, 1999, Bone, 25, 255, 10.1016/S8756-3282(99)00162-3 · DOI
- Horwood, 1998, Endocrinology, 139, 4743, 10.1210/endo.139.11.6433 · DOI
- Kitazawa, 1994, J Clin Invest, 94, 2397, 10.1172/JCI117606 · DOI
- Thomson, 1987, J Immunol, 138, 775, 10.4049/jimmunol.138.3.775 · DOI
- Lerner, 1993, J Bone Miner Res, 8, 147, 10.1002/jbmr.5650080205 · DOI
- van der Pluijm, 1991, Endocrinology, 129, 1596, 10.1210/endo-129-3-1596 · DOI
- Simonet, 1997, Cell, 89, 309, 10.1016/S0092-8674(00)80209-3 · DOI · Paper page
- Iotsova, 1997, Nat Med, 11, 1285, 10.1038/nm1197-1285 · DOI
- Grigoriadis, 1994, Science, 266, 443, 10.1126/science.7939685 · DOI
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HIRAYAMA, T. (2002) · British journal of rheumatology · doi:10.1093/rheumatology/41.11.1232 · Cited by 127
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Sokos, D., Everts, V. E., & de Vries, T. J. (2014) · Journal of Periodontal Research · doi:10.1111/jre.12197 · Cited by 141
Bonar, S. L., Brydges, S., Mueller, J., McGeough, M. D., Peña, C., Chen, D., Grimston, S., Hickman-Brecks, C. L., Ravindran, S., McAlinden, A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035979 · Cited by 130
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BackgroundBull, M. J., Williams, A. S., Mecklenburgh, Z., Calder, C. J., Twohig, J. P., Elford, C., Evans, B. A. J., Rowley, T. F., Ślebioda, T. J., Taraban, V. Y., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20072378 · Cited by 114
Bone loss in inflammatory arthritis: mechanisms and treatment strategies
Walsh, N. C., & Gravallese, E. M. (2004) · Current Opinion in Rheumatology · doi:10.1097/01.bor.0000127824.42507.68 · Cited by 118
Targeting tumor–stromal interactions in bone metastasis
Esposito, M., & Kang, Y. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.10.006 · Cited by 129
Schett, G. A., & Teitelbaum, S. L. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.090533 · Cited by 126
“This process, however, requires at least constitutive amounts of RANKL, which ‘‘primes’’ macrophages to commit to the osteoclast phenotype in response to TNF.(40) In a reciprocal fashion, TNF ‘‘primes’’ these precursors to undergo osteoclast differentiation in response to relatively small amounts of RANKL.”
BackgroundSelf-citationMcNamara, L. M. (2009) · Journal of The Royal Society Interface · doi:10.1098/rsif.2009.0282 · Cited by 124
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Roodman, G. D., & Dougall, W. C. (2007) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2007.09.002 · Cited by 127
Osteoclast formation and differentiation: an overview.
Soysa, N., Alles, N., Aoki, K., & Ohya, K. (2012) · Journal of Medical and Dental Sciences · doi:10.11480/jmds.590301 · Cited by 127
Finzel, S., Rech, J., Schmidt, S., Engelke, K., Englbrecht, M., Stach, C., & Schett, G. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.148395 · Cited by 126
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BackgroundHolding, C., Findlay, D. M., Stamenkov, R., Neale, S., Lucas, H., Dharmapatni, A. A. S. S. K., Callary, S., Shrestha, K., Atkins, G., Howie, D., et al. (2006) · Biomaterials · doi:10.1016/j.biomaterials.2006.05.054 · Cited by 126
“osteoclastogenesis, TNFa did induce osteoclastogenesis both in vitro and in vivo in the presence of permissive levels of RANKL [32].”
BackgroundOverexpression of microRNA-223 in rheumatoid arthritis synovium controls osteoclast differentiation
Shibuya, H., Nakasa, T., Adachi, N., Nagata, Y., Ishikawa, M., Deie, M., Suzuki, O., & Ochi, M. (2012) · Modern Rheumatology · doi:10.1007/s10165-012-0710-1 · Cited by 127
“Understanding intracellular signaling pathways from the analysis of RANKL, osteoprotegerin (OPG), and other markers has helped elucidate osteoclast differentiation and activation [23, 24].”
BackgroundIL-7 Up-Regulates TNF-α-Dependent Osteoclastogenesis in Patients Affected by Solid Tumor
Roato, I., Brunetti, G., Gorassini, E., Grano, M., Colucci, S., Bonello, L., Buffoni, L., Manfredi, R., Ruffini, E., Ottaviani, D., et al. (2006) · PLoS ONE · doi:10.1371/journal.pone.0000124 · Cited by 125
Kagiya, T., & Nakamura, S. (2012) · Journal of Periodontal Research · doi:10.1111/jre.12017 · Cited by 113
IL‐17 mediates estrogen‐deficient osteoporosis in an Act1‐dependent manner
DeSelm, C. J., Takahata, Y., Warren, J. T., Chappel, J. C., Khan, T., Li, X., Liu, C., Choi, Y., Kim, Y. F., Zou, W., et al. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24165 · Cited by 132
“Additionally, TNF and IL-1 synergize with the osteoclastogenic cytokine to directly stimulate precursor differentiation into the mature resorptive polykaryon [Lam et al., 2000; Wei et al., 2005].”
BackgroundSelf-citationSchett, G., Coates, L., Ash, Z., Finzel, S., & Conaghan, P. (2011) · Arthritis Research & Therapy · doi:10.1186/1478-6354-13-s1-s4 · Cited by 124
“Addition of TNF to monocyte cultures challenged with macrophage colony-stimulating factor and receptor activator of NF-κB ligand (molecules that activate osteo clasts, which are the cells involved in bone resorption) enhances the formation of osteoclasts, and overexpres sion of TNF in mice entails increased formation…”
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Tsukasaki, M., Huynh, N. C., Okamoto, K., Muro, R., Terashima, A., Kurikawa, Y., Komatsu, N., Pluemsakunthai, W., Nitta, T., Abe, T., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00318-y · Cited by 142
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Harris, V. W., & Brown, T. T. (2012) · The Journal of Infectious Diseases · doi:10.1093/infdis/jis199 · Cited by 122
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BackgroundHow antirheumatic drugs protect joints from damage in rheumatoid arthritis
Schett, G. A., Stach, C. M., Zwerina, J., Voll, R. E., & Manger, B. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23951 · Cited by 115
Zhai, Z., Li, H. W., Liu, G. W., Qu, X., Tian, B., Yan, W., Lin, Z., Tang, T., Qin, A., & Dai, K. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12463 · Cited by 123
“There is a strong consensus that TNFα and RANKL can act synergistically to induce osteoclastogenesis (Lam et al., 2000; Komine et al., 2001; Zou et al., 2001) but whether TNFα alone is sufficient for osteoclast formation is still controversial (Kobayashi et al.”
BackgroundMyeloma bone disease: pathophysiology and management
Terpos, E., & Dimopoulos, M. A. (2005) · Annals of Oncology · doi:10.1093/annonc/mdi235 · Cited by 238
“The effects of TNF-a are mediated by stimulation of the proteolytic breakdown of Ikappa B [the inhibitor of nuclear factor-kappa B (NF-kB)], leading to NF-kB activation and enhancement of gene transcription, including IL-6 and adhesion molecules, which are involved in promoting bone resorption [6].”
BackgroundMohamed, S. G.-K., Sugiyama, E., Shinoda, K., Taki, H., Hounoki, H., Abdel-Aziz, H. O., Maruyama, M., Kobayashi, M., Ogawa, H., & Miyahara, T. (2007) · Bone · doi:10.1016/j.bone.2007.05.016 · Cited by 120
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BackgroundInflammatory Processes Affecting Bone Health and Repair
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Osteoimmunology in rheumatic diseases
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BackgroundLi, S.-J., Zhang, L., Liu, C.-Y., Kim, J., Su, K., Chen, T., Zhao, L., Lu, X., Zhang, H., Cui, Y.-L., et al. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.10.021 · Cited by 119
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BackgroundShu, L., Beier, E. E., Tzong, S. J., Zhang, H., Zuscik, M., Puzas, J., Boyce, F. B., Mooney, A., & Xing, L. (2015) · Calcified Tissue International · doi:10.1007/s00223-015-9954-z · Cited by 119
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Ibáñez, L., Abou-Ezzi, G., Ciucci, T., Amiot, V., Belaïd, N., Obino, D., Mansour, A., Rouleau, M., Wakkach, A., & Blin-Wakkach, C. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2868 · Cited by 117
“TNFa is a potent activator of osteoclastogenesis((38,39)) and TNFaþ T cells have been described to increase bone resorption in ovariectomized mice.”
BackgroundFakruddin, J. M., & Laurence, J. (2004) · Archives of Virology · doi:10.1007/s00705-004-0395-7 · Cited by 117
“7 cells into TRAP+ multinucleated cells capable of bone resorption [23].”
BackgroundCoulson, K. A., Reed, G. W., Gilliam, B. E., Kremer, J. M., & Pepmueller, P. H. (2009) · JCR Journal of Clinical Rheumatology · doi:10.1097/rhu.0b013e3181a5679d · Cited by 124
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Feng, W., Liu, H., Luo, T., Liu, D., Du, J., Sun, J., Wang, W., Han, X., Yang, K., Guo, J., et al. (2017) · Scientific Reports · doi:10.1038/srep41411 · Cited by 121
Thummuri, D., Jeengar, M. K., Shrivastava, S., Nemani, H., Naik, R. R., Chaudhari, P. R., & Naidu, V. G. M. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.05.006 · Cited by 125
Yasui, T., Kadono, Y., Nakamura, M., Oshima, Y., Matsumoto, T., Masuda, H., Hirose, J., Omata, Y., Yasuda, H., Imamura, T., et al. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.357 · Cited by 114
Liu, D., Yao, S., & Wise, G. E. (2006) · European Journal of Oral Sciences · doi:10.1111/j.1600-0722.2006.00283.x · Cited by 113
Zauli, G., Rimondi, E., Nicolin, V., Melloni, E., Celeghini, C., & Secchiero, P. (2004) · Blood · doi:10.1182/blood-2004-03-1196 · Cited by 115
O' Gradaigh, D., Ireland, D., Bord, S., & Compston, J. E. (2004) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2003.008458 · Cited by 111
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Ochi, S., Shinohara, M., Sato, K., Gober, H.-J., Koga, T., Kodama, T., Takai, T., Miyasaka, N., & Takayanagi, H. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701971104 · Cited by 123
Herrak, P., Görtz, B., Hayer, S., Redlich, K., Reiter, E., Gasser, J., Bergmeister, H., Kollias, G., Smolen, J. S., & Schett, G. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20384 · Cited by 110
Atkins, G., Welldon, K. J., Holding, C., Haynes, D., Howie, D., & Findlay, D. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.03.035 · Cited by 110
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Lin, T., Pajarinen, J., Lu, L. Y., Nabeshima, A., Córdova, L. A., Yao, Z., & Goodman, S. B. (2016) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2016.11.002 · Cited by 123
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Virk, M. S., & Lieberman, J. R. (2007) · Arthritis Research & Therapy · doi:10.1186/ar2169 · Cited by 101
Miranda‐Carús, M., Benito, M., Balsa, A., Cobo‐Ibáñez, T., de Ayala, C. P., Pascual‐Salcedo, D., & Martín-Mola, E. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21731 · Cited by 93
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“However, whether an independent role for TNF-α in osteoclast differentiation exists remains controversial, as the continuous presence of OPG has been shown to interfere with in vitro TNF-α-induced osteoclastogenesis [71].”
Bisphosphonates: effects on osteoblast
Maruotti, N., Corrado, A., Neve, A., & Cantatore, F. P. (2012) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-012-1216-7 · Cited by 106
Immune regulation of bone loss by Th17 cells
Adamopoulos, I. E., & Bowman, E. P. (2008) · Arthritis Research & Therapy · doi:10.1186/ar2502 · Cited by 101
From osteoimmunology to osteomicrobiology: How the microbiota and the immune system regulate bone
Hsu, E., & Pacifici, R. (2018) · Calcified Tissue International · doi:10.1007/s00223-017-0321-0 · Cited by 106
“Assessment of cytokine production revealed that sex steroid deficiency expands TNF and IL-17 producing T cells, and increases the levels of TNF, RANKL and IL-17 protein in the bone marrow and in the small intestine of conventionally raised mice.”
InfluentialGartland, A., Buckley, K. A., Bowler, W. B., & Gallagher, J. (2003) · Calcified Tissue International · doi:10.1007/s00223-002-2098-y · Cited by 106
“, a late-stage event) [35, 36] —did increase the expression of P2X7 receptor mRNA in RANKL-generated human osteoclasts.”
BackgroundThe Interplay between Immune System and Microbiota in Osteoporosis
Locantore, P., Gatto, V. D., Gelli, S., Paragliola, R. M., & Pontecorvi, A. (2020) · Mediators of Inflammation · doi:10.1155/2020/3686749 · Cited by 117
“Moreover, lymphocytes produce tumor necrosis factor α (TNFα) and interleukin (IL)-17, both involved in osteoclastogenesis [35, 36].”
BackgroundPavlos, N., Xu, J.-K., Riedel, D., Yeoh, J. S. G., Teitelbaum, S., Papadimitriou, J., Jahn, R., Ross, F., & Zheng, M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.12.5253-5269.2005 · Cited by 105
Self-citationIbáñez, L., Rouleau, M., Wakkach, A., & Blin-Wakkach, C. (2019) · Joint Bone Spine · doi:10.1016/j.jbspin.2018.02.008 · Cited by 103
Tan, E. M., & Smolen, J. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20160792 · Cited by 103
“TNF, in turn, amplifies osteoclastogenesis, especially in the presence of receptor activator of NF-κB ligand (RAN KL; Lam et al., 2000; Binder et al., 2013).”
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Danks, L., Sabokbar, A., Gundle, R., & Athanasou, N. (2002) · Annals of the Rheumatic Diseases · doi:10.1136/ard.61.10.916 · Cited by 103
Algate, K., Haynes, D. R., Bartold, P. M., Crotti, T. N., & Cantley, M. D. (2015) · Journal of Periodontal Research · doi:10.1111/jre.12339 · Cited by 108
Clohisy, J. C. F., Frazier, E. P., Hirayama, T., & Abu‐Amer, Y. (2003) · Journal of Orthopaedic Research® · doi:10.1016/s0736-0266(02)00133-x · Cited by 92
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Pacifici, R. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031203 · Cited by 101
“2001), in which the key mechanisms by which TNF stimulates bone resorption were identified as the potentiation of RANKL activity (Cenci et al. 2000; Lam et al. 2000) and induction of Th17 cells (Chen et al.”
BackgroundOsteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases
Coury, F., Peyruchaud, O., & Machuca‐Gayet, I. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00679 · Cited by 110
Drosatos-Tampakaki, Z., Drosatos, K., Siegelin, Y., Gong, S., Khan, S., Dyke, T. V., Goldberg, I., Schulze, P. C., & Schulze-Späte, U. (2014) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2150 · Cited by 101
“Given the contribution of inflammation to bone degradation((6,7,9,11)) and impaired bone formation,((62,63)) the pro‐inflammatory nature of PA may account for its aggravating impact on bone health by either promoting osteoclast or inhibiting osteoblast formation.”
BackgroundKitaura, H., Marahleh, A., Ohori, F., Noguchi, T., Nara, Y., Pramusita, A., Kinjo, R., Ma, J., Kanou, K., & Mizoguchi, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031481 · Cited by 106
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Alippe, Y., Wang, C., Ricci, B., Xiao, J.-Q., Qu, C., Zou, W., Novack, D., Abu-Amer, Y., Civitelli, R., & Mbalaviele, G. (2017) · Scientific Reports · doi:10.1038/s41598-017-07014-0 · Cited by 100
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Kim, H., Choi, H. K., Shin, J. H., Kim, K., Huh, J. Y., Lee, S. A., Ko, C., Kim, H.-S., Shin, H.-I., Jeong, D., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36809 · Cited by 106
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Weitzmann, M. N., & Pacifici, R. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1346.030 · Cited by 92
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BackgroundOfotokun, I., McIntosh, E. B., & Weitzmann, M. N. (2011) · Current HIV/AIDS Reports · doi:10.1007/s11904-011-0099-z · Cited by 99
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Clohisy, J. C. F., Roy, B. C., Biondo, C., Frazier, E. P., Willis, D., Teitelbaum, S. L., & Abu‐Amer, Y. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.10.5547 · Cited by 90
“In fact the cytokine, acting through its type 1 receptor, heightens basal RANKL-generated osteoclasts in vitro, and permissive levels of the latter cytokine are sufficient to mediate TNF-induced osteoclast recruitment (10, 38, 39).”
BackgroundSelf-citationRagab, A. A., Nalepka, J. L., Bi, Y.-M., & Greenfield, E. (2002) · American Journal of Physiology - Cell Physiology · doi:10.1152/ajpcell.00421.2001 · Cited by 99
Yip, K., Zheng, M. H., Feng, H.-T., Steer, J., Joyce, D., & Xu, J.-K. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040919 · Cited by 98
“These mediators, in turn, contribute to the activation of osteoclasts and the induction of osteoclastogenesis.((5,37,38)) Therefore, inhibition of NF- B activation by PAR could also attenuate the LPS-induced production of these mediators, and consequently, their actions in chronic inflammation and osteolysis.”
BackgroundRheumatoid Arthritis in the View of Osteoimmunology
Auréal, M., Machuca‐Gayet, I., & Coury, F. (2020) · Biomolecules · doi:10.3390/biom11010048 · Cited by 126
“Secondly, TNF directly stimulates the differentiation of osteoclasts from mononuclear precursors in synovial tissues in synergy with RANKL [73] (Figure 2).”
BackgroundThe Alternative Faces of Macrophage Generate Osteoclasts
Lampiasi, N., Russo, R., & Zito, F. (2016) · BioMed Research International · doi:10.1155/2016/9089610 · Cited by 114
Zinc-containing bioactive glasses for bone regeneration, dental and orthopedic applications
Balasubramanian, P., Strobel, L., Kneser, U., & Boccaccini, A. (2015) · doi:10.1515/bglass-2015-0006 · Cited by 97
“NF-κB is used as amajor pathway by both RANKL (receptor activator of NF-κB ligand) and TNFα (tumor necrosis factor α) to stimulate osteoclastogenesis [97].”
MethodDendritic Cells at the Osteo‐Immune Interface: Implications for Inflammation‐Induced Bone Loss
Alnaeeli, M., Park, J.-A., Mahamed, D., Penninger, J. M., & Teng, Y. (2007) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.070314 · Cited by 97
Komatsu, N., & Takayanagi, H. (2012) · Advances in immunology · doi:10.1016/b978-0-12-394299-9.00002-3 · Cited by 93
“as well as indirectly, by upregulating the production of M-CSF and RANKL on mesenchymal cells (Abu-Amer et al., 2000; Lam et al., 2000).”
New immune connections in osteoclast formation
Takayanagi, H. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05303.x · Cited by 93
TRAF2 Is Essential for TNF-α-Induced Osteoclastogenesis
Kanazawa, K., & Kudō, A. (2005) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.041225 · Cited by 100
“TNF- has the potential to induce osteoclast differentiation,((1,6,7)) and TNF- together with soluble RANKL strongly promotes osteoclast differentiation and activation in vitro.((7,8)) Recently, TNF- has become noteworthy as a”
BackgroundKahl, K. G., Rudolf, S., Stoeckelhuber, B. M., DIBBELT, L., Gehl, H., Markhof, K., Hohagen, F., & Schweiger, U. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.1.168 · Cited by 98
Ofotokun, I., Titanji, K., Vunnava, A., Roser-Page, S., Vikulina, T., Villinger, F., Rogers, K., Sheth, A., Lahiri, C. D., Lennox, J., et al. (2016) · AIDS (London) · doi:10.1097/qad.0000000000000918 · Cited by 94
Pacheco, R. A., & Stock, H. (2013) · Current Osteoporosis Reports · doi:10.1007/s11914-013-0174-z · Cited by 94
“There is a near immediate reduction in the number of osteoblasts post radiation therapy, hypothesized to occur secondary to cell cycle arrest rather than direct radiation-induced cell death [7, 8].”
Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link
Sapir‐Koren, R., & Livshits, G. (2017) · Bone · doi:10.1016/j.bone.2017.06.020 · Cited by 99
Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss
Tawfeek, H. A. W., Bedi, B., Li, J., Adams, J., Kobayashi, T., Weitzmann, M. N., Kronenberg, H. M., & Pacifici, R. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012290 · Cited by 92
“TNF is known to stimulate bone resorption and causes bone loss by potentiating the osteoclastogenic activity of RANKL produced in the BM microenvironment [43,44] and by increasing the production of RANKL by SCs and OBs via activation of the NFkB and JNK signaling pathways [45].”
BackgroundColucci, S., Brunetti, G., Cantatore, F., Oranger, A., Mori, G., Quarta, L., Cirulli, N., Mancini, L., Corrado, A., Grassi, F. R., et al. (2007) · Journal of Pathology · doi:10.1002/path.2153 · Cited by 92
“It has been demonstrated that very small quantities of RANKL are sufficient to synergize with tumour necrosis factor α (TNFα) and potentiate osteoclastogenesis [9].”
BackgroundInhibition of p38 Mitogen-Activated Protein Kinase Prevents Inflammatory Bone Destruction
Mbalaviele, G., Anderson, G. D., Jones, A., Ciechi, P. D., Settle, S., Mnich, S., Thiede, M. A., Abu‐Amer, Y., Portanova, J. P., & Monahan, J. B. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.100362 · Cited by 87
“Recent studies that addressed this issue concluded that TNF- , for example, promotes osteoclastogenesis in synergy with RANKL (Lam et al., 2000; Komine et al., 2001).”
BackgroundOsteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection
Jones, D. C., Glimcher, L. H., & Aliprantis, A. O. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46262 · Cited by 93
Vandooren, B., Cantaert, T., Noordenbos, T., Tak, P. P., & Baeten, D. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23290 · Cited by 78
Bone Metastasis Pain, from the Bench to the Bedside
Aielli, F., Ponzetti, M., & Rucci, N. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020280 · Cited by 92
Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling
AlQranei, M. S., Senbanjo, L. T., Aljohani, H., Hamza, T., & Chellaiah, M. A. (2021) · BMC Immunology · doi:10.1186/s12865-021-00409-9 · Cited by 99
Zhou, J., Ye, S., Fujiwara, T., Manolagas, S. C., & Zhao, H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.478750 · Cited by 88
Osteoimmunology: The Crosstalk between T Cells, B Cells, and Osteoclasts in Rheumatoid Arthritis
Yang, M., & Zhu, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052688 · Cited by 83
“Mecha-nistically, TNF-α promotes osteoclasts by increasing the expression of RANK and its ligand RANKL [89,90].”
BackgroundBiologic therapies and systemic bone loss in rheumatoid arthritis
Dimitroulas, T., Nikas, S. N., Trontzas, P., & Kitas, G. D. (2013) · Autoimmunity Reviews · doi:10.1016/j.autrev.2013.03.015 · Cited by 80
“For example TNF-alpha exerts direct effects on osteoclast precursors by inducing the expression of receptors such as TNF-receptor type-1 on the surface of monocytes, stimulating their differentiation to osteoclasts [43].”
BackgroundFrom bone biology to clinical outcome: state of the art and future perspectives
Schett, G. A., Saag, K. G., & Bijlsma, J. W. J. (2010) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.135061 · Cited by 86
Ma, T., Miyanishi, K., Suen, A., Epstein, N. J., Tomita, T., Smith, R. L., & Goodman, S. (2004) · Cytokine · doi:10.1016/j.cyto.2004.02.001 · Cited by 88
Takahashi, N., Udagawa, N., Takami, M., & Suda, T. (2002) · Elsevier eBooks · doi:10.1016/b978-012098652-1/50109-8 · Cited by 151
Hascoët, E., Blanchard, F., Blin‐Wakkach, C., Guicheux, J., Lesclous, P., & Cloître, A. (2023) · Bone Research · doi:10.1038/s41413-023-00257-w · Cited by 92
Macrophages and Intervertebral Disc Degeneration
Koroth, J., Buko, E. O., Abbott, R., Johnson, C. P., Ogle, B. M., Stone, L. S., Ellingson, A. M., & Bradley, E. W. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021367 · Cited by 92
Key roles of the OPG–RANK–RANKL system in bone oncology
Baud’huin, M., Duplomb, L., Velasco, C. R., Fortun, Y., Heymann, D., & Padrines, M. (2007) · Expert Review of Anticancer Therapy · doi:10.1586/14737140.7.2.221 · Cited by 84
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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