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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Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.
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
RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism.
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

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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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Yu, B., Chang, J., Liu, Y., Li, J., Kevork, K., Al‐Hezaimi, K., Graves, D. T., Park, N.-H., & Wang, C. (2014) · Nature Medicine · doi:10.1038/nm.3586 · Cited by 235
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“ulated with hormones or cytokines (32, 34, 48, 69).”
Background
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“text, because release of HMGB1 is elicited by lipopolysaccharide and multiple inflammatory mediators (IL-1, TNF , interferon- and - ), we propose that the HMGB1–RAGE interaction could represent a final common pathway in inflammation-associated bone resorption.((9,35,39))”
Background
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Background
Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-κB transactivation by RANKL
Huang, H., Ryu, J., Ha, J., Chang, E.-J., Kim, H. J., Kim, H.-M., Kitamura, T., Lee, Z. H., & Kim, H. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401882 · Cited by 156
Macrophages and Bone Remodeling
Weivoda, M. M., & Bradley, E. W. (2023) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4773 · Cited by 166
“Inflammatory mediators produced by macrophages, including IFN-γ, TNF-α, and IL-6, promote either the proliferation of pre-osteoclast cells or osteoclast differentiation.((74-81)) Moreover, pro-inflammatory macrophage cytokines (eg, TNF-α, IL-6) promote apoptosis of osteocytes.”
Background
N ew M olecules in the T umor N ecrosis F actor L igand and R eceptor S uperfamilies with I mportance for P hysiological and P athological B one R esorption
Lerner, U. H. (2004) · Critical Reviews in Oral Biology & Medicine · doi:10.1177/154411130401500202 · Cited by 147
TNF and Bone Remodeling
Zhao, B. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0358-z · Cited by 178
TWEAK Mediates Signal Transduction and Differentiation of RAW264.7 Cells in the Absence of Fn14/TweakR
Polek, T. C., Talpaz, M., Darnay, B. G., & Spivak-Kroizman, T. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302518200 · Cited by 139
High Levels of Tumor Necrosis Factor-α Contribute to Accelerated Loss of Cartilage in Diabetic Fracture Healing
Alblowi, J. A., Kayal, R. A., Siqueria, M., McKenzie, E., Krothapalli, N., McLean, J., Conn, J., Nikolajczyk, B. S., Einhorn, T. A., Gerstenfeld, L. C., et al. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.090148 · Cited by 149
Tumor necrosis factor‐α mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism†
Zou, W., Hakim, I., Tschoep, K., Endres, S., & Bar‐Shavit, Z. (2001) · Journal of Cellular Biochemistry · doi:10.1002/jcb.1202 · Cited by 143
“Recently [Lam et al., 2000], using immunopuri®ed myeloid cells, it was shown that TNF-a induces osteoclastic differentiation only in RANKL primed cells.”
Method
RANKL protein is expressed at the pannus–bone interface at sites of articular bone erosion in rheumatoid arthritis
Pettit, A. R., Walsh, N. C., Manning, C., Goldring, S. R., & Gravallese, E. M. (2006) · Rheumatology · doi:10.1093/rheumatology/kel045 · Cited by 151
“The pro-inflammatory cytokines TNF and interleukin (IL)-1 can regulate osteoclast differentiation and function in the presence of RANKL in vitro [44–49].”
Background
Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation
Grassi, F., Tell, G., Robbie-Ryan, M., Gao, Y., Terauchi, M., Yang, X., Romanello, M., Jones, D. P., Weitzmann, M. N., & Pacifici, R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703610104 · Cited by 150
Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells
Yu, M., Pal, S., Paterson, C. W., Li, J., Tyagi, A. M., Adams, J., Coopersmith, C. M., Weitzmann, M. N., & Pacifici, R. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143137 · Cited by 173
“The primary drivers of increased osteoclastogenesis are enhanced production of the immune factors RANKL, TNF, and IL-17 and decreased secretion of the RANKL antagonist osteoprotegerin (OPG) (1, 5).”
BackgroundResultInfluential
Osteoclasts; culprits in inflammatory osteolysis.
Teitelbaum, S. L. (2005) · Arthritis Research & Therapy · doi:10.1186/ar1857 · Cited by 138
Self-citation
Molecular analysis of RANKL‐independent cell fusion of osteoclast‐like cells induced by TNF‐α, lipopolysaccharide, or peptidoglycan
Hotokezaka, H., Sakai, E., Ohara, N., Hotokezaka, Y., Gonzales, C., Matsuo, K., Fujimura, Y., Yoshida, N., & Nakayama, K. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21167 · Cited by 137
“Furthermore, TNF-a was reported to induce osteoclastogenesis in macrophages exposed to permissive levels of RANKL [Lam et al., 2000].”
Background
The Osteoclast in Bone Metastasis: Player and Target
Maurizi, A., & Rucci, N. (2018) · Cancers · doi:10.3390/cancers10070218 · Cited by 165
“Indeed, TNFα induces osteoclast differentiation directly by activating NF-κB and JNK (c-Jun N-terminal kinases) in a RANKL-independent manner [52] and indirectly by stimulating the osteoblasts to express RANKL [53].”
Background
Novel insights into macrophage diversity in rheumatoid arthritis synovium.
Boutet, M., Courties, G., Nerviani, A., le Goff, B., Apparailly, F., Pitzalis, C., & Blanchard, F. (2021) · Autoimmunity Reviews · doi:10.1016/j.autrev.2021.102758 · Cited by 147
Macrophage-Specific TLR2 Signaling Mediates Pathogen-Induced TNF-Dependent Inflammatory Oral Bone Loss
Papadopoulos, G., Weinberg, E. O., Massari, P., Gibson, F. C., Wetzler, L. M., Morgan, E. F., & Genco, C. A. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202511 · Cited by 151
“TNF works in synergy with RANKL to promote the activation and differentiation of osteoclasts (50, 51).”
Background
Estrogen deficiency, T cells and bone loss
Pacifici, R. (2008) · Cellular Immunology · doi:10.1016/j.cellimm.2007.06.008 · Cited by 146
Cytokine-Mediated Bone Destruction in Rheumatoid Arthritis
Jung, S. M., Kim, K., Yang, C. W., Park, S., & Ju, J. H. (2014) · Journal of Immunology Research · doi:10.1155/2014/263625 · Cited by 165
Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats
Vikulina, T., Fan, X., Yamaguchi, M., Roser-Page, S., Zayzafoon, M., Guidot, D., Ofotokun, I., & Weitzmann, M. (2010) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1003020107 · Cited by 145
The immune system and bone
Pacifici, R. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.05.027 · Cited by 120
Transcription factor C/EBPβ isoform ratio regulates osteoclastogenesis through MafB
Smink, J. J., Bégay, V., Schoenmaker, T., Sterneck, E., de Vries, T. J., & Leutz, A. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.127 · Cited by 130
“Autocrine TNFa production in osteoclasts derived from c/ebpb / or L/L mice indeed contributed to augmented osteoclastogenesis, consistent with earlier reports (Lam et al, 2000; Fuller et al, 2002; Kim et al, 2008).”
BackgroundResult
Docosahexaenoic acid is more potent inhibitor of osteoclast differentiation in RAW 264.7 cells than eicosapentaenoic acid
Rahman, M. M., Bhattacharya, A., & Fernandes, G. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21188 · Cited by 139
TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL.
Fuller, K., Murphy, C., Kirstein, B., Fox, S., & Chambers, T. (2002) · Endocrinology · doi:10.1210/en.143.3.1108 · Cited by 145
“One explanation for the discrepant effects of TNF and RANKL in vivo would be that TNF induces osteoclastic differentiation only in precursors primed by RANKL (14).”
BackgroundInfluential
IFN‐γ‐producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL
Kotake, S., Nanke, Y., Mogi, M., Kawamoto, M., Furuya, T., Yago, T., Kobashigawa, T., Togari, A., & Kamatani, N. (2005) · European Journal of Immunology · doi:10.1002/eji.200526141 · Cited by 144
Severity of obstructive airway disease and risk of osteoporotic fracture
de Vries, F., van Staa, T. P., Bracke, M., Cooper, C. C., Leufkens, H. G. M., & Lammers, J. J. (2005) · European Respiratory Journal · doi:10.1183/09031936.05.00058204 · Cited by 136
Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment
Aletaha, D., Funovits, J., Breedveld, F. C., Sharp, J. T., Segurado, O. G., & Smolen, J. S. (2009) · Arthritis & Rheumatism · doi:10.1002/art.24433 · Cited by 139
Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis.
Funk, J. L., Frye, J., Oyarzo, J., Kuscuoglu, N., Wilson, J., Mccaffrey, G., Stafford, G., Chen, G.-J., Lantz, R., Jolad, S., et al. (2006) · Arthritis & Rheumatism · doi:10.1002/art.22180 · Cited by 143
Neutrophils: Novel key players in Rheumatoid Arthritis. Current and future therapeutic targets
Cecchi, I., de la Rosa, I. A., Menegatti, E., Roccatello, D., Collantes‐Estévez, E., López-Pedrera, C., & Barbarroja, N. (2018) · Autoimmunity Reviews · doi:10.1016/j.autrev.2018.06.006 · Cited by 174
Bacterial lipopolysaccharide induces osteoclast formation in RAW 264.7 macrophage cells
Islam, S., Hassan, F., Tumurkhuu, G., Dagvadorj, J., Koide, N., Naiki, Y., Mori, I., Yoshida, T., & Yokochi, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.06.023 · Cited by 136
Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen‐induced arthritis
Sims, N. A., Green, J. R., Glatt, M., Schlicht, S., Martin, T. J., Gillespie, M. T., & Romas, E. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20382 · Cited by 127
RANK‐Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis
O’Brien, W. M., Fissel, B. M., MAEDA, Y. Y., Yan, J., Ge, X., Gravallese, E. M., Aliprantis, A. O., & Charles, J. F. (2016) · Arthritis & Rheumatology · doi:10.1002/art.39837 · Cited by 152
Review: Immune cells and mediators of inflammatory arthritis
Schett, G. A. (2008) · Autoimmunity · doi:10.1080/08916930701694717 · Cited by 120
12-O-tetradecanoylphorbol-13-acetate (TPA) Inhibits Osteoclastogenesis by Suppressing RANKL-Induced NF-κB Activation
Wang, C., Steer, J. H., Joyce, D. A., Yip, K. H. M., Zheng, M., & Xu, J. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.12.2159 · Cited by 138
“cDNA-Jun-(1-135) was expressed as glutathione S-transferase (GST) fusion proteins and purified by glutathione-Sepharose chromatography for use as substrates for JNK assays.”
BackgroundMethod
Interleukin-1 is essential for systemic inflammatory bone loss
Polzer, K., Joosten, L. A. B., Gasser, J. A., Distler, J. H. W., Ruiz, G., Baum, W., Redlich, K., Bobacz, K., Smolen, J. S., van den Berg, W., et al. (2009) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.104786 · Cited by 143
“TNF is considered as a major enhancer of osteoclastogenesis by driving the expression of RANKL and by directly increasing the differentiation of osteoclast precursors and enhancing the resorptive activity.”
Background
Akermanite bioceramics promote osteogenesis, angiogenesis and suppress osteoclastogenesis for osteoporotic bone regeneration
Xia, L., Yin, Z., Mao, L., Wang, X., Liu, J., Jiang, X., Zhang, Z., Lin, K., Chang, J., & Fang, B. (2016) · Scientific Reports · doi:10.1038/srep22005 · Cited by 140
Antioxidant α-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-κB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-κB ligand and tumor necrosis factor-α
Kim, H. J., Chang, E.-J., Kim, H.-M., Lee, S., Kim, H.-D., Kim, G., & Kim, H.-H. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.10.066 · Cited by 136
“TNF-α is a potential candidate for inducing ROS in osteoclast lineage cells because it exerts strong effects on osteoclast differentiation [7] and has been shown to cause ROS generation in other cell types [13,21].”
Background
A TNF receptor loop peptide mimic blocks RANK ligand–induced signaling, bone resorption, and bone loss
Aoki, K., Saito, H., Itzstein, C., Ishiguro, M., Shibata, T., Blanqué, R., Mian, A. H., Takahashi, M., Suzuki, Y., Yoshimatsu, M., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci22513 · Cited by 136
Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis.
Redlich, K., Görtz, B., Hayer, S., Zwerina, J., Doerr, N., Kostenuik, P., Bergmeister, H., Kollias, G., Steiner, G., Smolen, J. S., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63144-6 · Cited by 134
“The effect is mediated by induction of RANKL expression and a synergistic effect with RANKL on nuclear factor- B and stress-activated/c-Jun NH(2)-terminal protein kinase, two signaling pathways essential for osteoclastogenesis.(8) With respect to the osteoblast lineage, however, TNF is considered a negative regulator…”
BackgroundMethod
Heme oxygenase 1 (HO‐1) regulates osteoclastogenesis and bone resorption
Zwerina, J., Tzima, S., Hayer, S., Redlich, K., Hoffmann, O., Hanslik‐Schnabel, B., Smolen, J. S., Kollias, G. A., & Schett, G. A. (2005) · The FASEB Journal · doi:10.1096/fj.05-4278fje · Cited by 130
Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis
Sabokbar, A., Kudo, O., & Athanasou, N. (2003) · Journal of Orthopaedic Research · doi:10.1016/s0736-0266(02)00106-7 · Cited by 134
Roles of osteoclasts in alveolar bone remodeling
Omi, M., & Mishina, Y. M. (2022) · genesis · doi:10.1002/dvg.23490 · Cited by 156
“Although these inflammatory cytokines do not substitute for RANKL in physiological conditions (Li et al., 2000), they prompt robust osteoclastogenesis in inflammatory conditions even without elevation of RANKL levels (Kobayashi et al., 2000; Lam et al., 2000).”
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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