Joint erosion in rheumatoid arthritis: interactions between tumour necrosis factor α, interleukin 1, and receptor activator of nuclear factor κB ligand (RANKL) regulate osteoclasts.
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Background Osteoclasts, specialised bone resorbing cells regulated by RANKL and M-CSF, are implicated in rheumatoid joint erosion. Lymphocyte-monocyte interactions activate bone resorption, this being attributed to tumour necrosis factor alpha (TNFalpha) and interleukin 1 beta (IL1beta) enhanced osteoblast expression of RANKL. In animal studies, TNF potently increases osteoclast formation in the presence of RANKL. RANKL-independent osteoclastogenesis also occurs, though IL1 is required for resorptive function in most studies. These inflammatory cytokines have a pivotal role in rheumatoid arthritis,Objective To study the interactions of TNFalpha and IL1beta with RANKL, particularly the time course of the interactions and the role of lymphocytes.Method Cultures of lymphocytes and monocytes (osteoclast precursors) or of purified CD14(+) cells alone (osteoclast precursors) were exposed to various combinations of TNFalpha, RANKL, and IL1beta or the inhibitors osteoprotegerin, IL1 receptor antagonist, or neutralising antibodies to RANKL or to IL1. Osteoclastogenesis and resorptive activity were assessed on microscopy of dentine slices.Results TNFalpha potently increased osteoclast proliferation/differentiation in the presence of RANKL. This effect was greatest when RANKL was present before but not after exposure of osteoclast precursor cells to TNFalpha. The resorptive activity of osteoclasts generated by TNFalpha in the absence of RANKL was critically dependent upon IL1, which was expressed by lymphocyte-monocyte interaction.Conclusion TNFalpha potently enhances RANKL mediated osteoclast activity. Interactions between TNFalpha and IL1 also result in osteoclastic activity independently of RANKL. These findings will inform therapeutic approaches to the prevention of joint erosion in rheumatoid arthritis.
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High circulating levels of TNF-α and IL-1, common in RA, have the potential to promote osteoclastogenesis throughout the skeleton.
“Certainly the high circulating levels of TNF-␣ and IL-1 that are common in RA have the potential to promote osteoclastogenesis throughout the skeleton (223,237,(423)(424)(425).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [424]
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Cites
Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S.-I., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.7.3597 · Cited by 4,224 · see citing works
Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis
Lipsky, P. E., van der Heijde, D. M. F. M., Clair, E. W. S., Fürst, D. E., Breedveld, F. C., Kalden, J. R., Smolen, J. S., Weisman, M. H., Emery, P., Feldmann, M., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200011303432202 · Cited by 2,990 · see citing works
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 · see citing works
Lam, J., Takeshita, S., Barker, J. E., Kanagawa, O., Ross, F. P., & Teitelbaum, S. L. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11176 · Cited by 1,440 · see citing works
Bertolini, D. R., Nedwin, G. E., Bringman, T. S., Smith, D. D., & Mundy, G. R. (1986) · Nature · doi:10.1038/319516a0 · Cited by 1,425 · see citing works
Kobayashi, K., Takahashi, N., Jimi, E., Udagawa, N., Takami, M., Kotake, S., Nakagawa, N., Kinosaki, M., Yamaguchi, K., Shima, N., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.2.275 · Cited by 1,304 · see citing works
TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis.
Pettit, A. R., Ji, H., von Stechow, D., Müller, R., Goldring, S. R., Choi, Y., Benoist, C., & Gravallese, E. M. (2001) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63016-7 · Cited by 807 · see citing works
Tumor Necrosis Factor-α Induces Differentiation of and Bone Resorption by Osteoclasts
Azuma, Y., Kaji, K., Katogi, R., Takeshita, S., & Kudo, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.7.4858 · Cited by 731 · see citing works
Hofbauer, L. C., Lacey, D. L., Dunstan, C. R., Spelsberg, T. C., Riggs, B. L., & Khosla, S. (1999) · Bone · doi:10.1016/s8756-3282(99)00162-3 · Cited by 630 · see citing works
Gravallese, E. M., Harada, Y., Wang, J. T., Gorn, A. H., Thornhill, T. S., & Goldring, S. R. (1998) · Europe PMC (PubMed Central) · Cited by 512 · see citing works
Dewhirst, F. E., Stashenko, P., Mole, J. E., & Tsurumachi, T. (1985) · The Journal of Immunology · doi:10.4049/jimmunol.135.4.2562 · Cited by 507 · see citing works
Zhang, Y.-H., Heulsmann, A., Tondravi, M. M., Mukherjee, A., & Abu‐Amer, Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008198200 · Cited by 496 · see citing works
́stergaard, M., Hansen, M. S., Stoltenberg, M., Gideon, P., Klarlund, M., Jensen, K. E., & Lorenzen, I. (1999) · Arthritis & Rheumatism · doi:10.1002/1529-0131(199905)42:5 · Cited by 323 · see citing works
Fuller, K., Murphy, C., Kirstein, B., Fox, S., & Chambers, T. (2002) · Endocrinology · doi:10.1210/endo.143.3.8701 · Cited by 322 · see citing works
Proinflammatory cytokine (TNFα/IL‐1α) induction of human osteoclast formation
Kudo, O., Fujikawa, Y., Itonaga, I., Sabokbar, A., Torisu, T., & Athanasou, N. (2002) · Journal of Pathology · doi:10.1002/path.1190 · Cited by 193 · see citing works
Crotti, T. N., Smith, M. D., Weedon, H., Ahern, M. J., Findlay, D. M., Kraan, M., Tak, P. P., & Haynes, D. R. (2002) · Annals of the Rheumatic Diseases · doi:10.1136/ard.61.12.1047 · Cited by 186 · see citing works
Erwig, L., Kluth, D., Walsh, G. M., & Rees, A. J. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.4.1983 · Cited by 178 · see citing works
Lader, C. S., & Flanagan, A. M. (1998) · Endocrinology · doi:10.1210/endo.139.7.6085 · Cited by 174 · see citing works
Komine, M., Kukita, A., Kukita, T., Ogata, Y., Hotokebuchi, T., & Kohashi, O. (2001) · Bone · doi:10.1016/s8756-3282(01)00420-3 · Cited by 137 · see citing works
A Novel Role of IL-15 in the Development of Osteoclasts: Inability to Replace Its Activity with IL-2
Ogata, Y., Kukita, A., Kukita, T., Komine, M., Miyahara, A., Miyazaki, S., & Kohashi, O. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.5.2754 · Cited by 134 · see citing works
Sabokbar, A., Kudo, O., & Athanasou, N. (2003) · Journal of Orthopaedic Research · doi:10.1016/s0736-0266(02)00106-7 · Cited by 134 · see citing works
Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis.
Hirayama, T., Danks, L., Sabokbar, A., & Athanasou, N. (2002) · Rheumatology · doi:10.1093/rheumatology/41.11.1232 · Cited by 131 · see citing works
Macrophage-Lymphocyte Synergy in the Production of Osteoclast Activating Factor
Horton, J. E., Oppenheim, J. J., Mergenhagen, S. E., & Raisz, L. G. (1974) · The Journal of Immunology · doi:10.4049/jimmunol.113.4.1278 · Cited by 120 · see citing works
Nicholson, G. C., Malakellis, M., Collier, F., Cameron, P. U., Holloway, W. R., Gough, T. J., Gregorio-King, C. C., Kirkland, M. A., & Myers, D. E. (2000) · PubMed · Cited by 119 · see citing works
NICHOLSON, G. C., MALAKELLIS, M., COLLIER, F. M., CAMERON, P. U., HOLLOWAY, W. R., GOUGH, T. J., GREGORIO-KING, C., KIRKLAND, M. A., & MYERS, D. E. (2000) · Clinical Science · doi:10.1042/cs0990133 · Cited by 107 · see citing works
Fujikawa, Y., Sabokbar, A., Neale, S. D., Itonaga, I., Torisu, T., & Athanasou, N. A. (2001) · Bone · doi:10.1016/s8756-3282(00)00453-1 · Cited by 90 · see citing works
The role of TNF-receptor family members and other TRAF-dependent receptors in bone resorption.
Gravallese, E. M., Galson, D. L., Goldring, S. R., & Auron, P. E. (2001) · Arthritis Research · doi:10.1186/ar134 · Cited by 81 · see citing works
Targeting interleukin‐1 in the treatment of rheumatoid arthritis
Dayer, J., & Bresnihan, B. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10168 · Cited by 81 · see citing works
TGF-β1 and IFN-γ Direct Macrophage Activation by TNF-α to Osteoclastic or Cytocidal Phenotype
Fox, S. W., Fuller, K., Bayley, K. E., Lean, J. M., & Chambers, T. J. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.9.4957 · Cited by 68 · see citing works
Massey, H. M., Scopes, J., Horton, M. A., & Flanagan, A. M. (2001) · Bone · doi:10.1016/s8756-3282(01)00432-x · Cited by 60 · see citing works
T cells: Pathogenic cells and therapeutic targets in rheumatoid arthritis
Yocum, D. E. (1999) · Seminars in Arthritis and Rheumatism · doi:10.1016/s0049-0172(99)80035-3 · Cited by 34 · see citing works
Gravellese (2000) · Pure Amsterdam UMC · doi:10.1002/1529-0131(200002)43:2 · Cited by 2 · see citing works
Neidhart (2000) · Pure Amsterdam UMC · doi:10.1002/1529-0131(200012)43:12 · Cited by 1 · see citing works
Romas (2000) · Pure Amsterdam UMC · doi:10.1002/1529-0131(200004)43:4
Shigeyama (2000) · doi:10.1002/1529-0131(200011)43:11
Pope (2001) · doi:10.1002/1529-0131(200106)44:6
Flagged first, then by citations
Research works printed but not linked: 6
- Romas E, Bakharevski O, Hards DK, Kartsogiannis V, Quinn JMW, Ryan PFJ, et al. Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis Rheum 2000;43:821-6.
- Gravallese EM, Manning C, Tsay T, Naito A, Pan C, Amento E, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 2000;43:250-8.
- Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis. Arthritis Rheum 2000;43:2619-33.
- Chabaud M, Miossec P. The combination of tumor necrosis factor a blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inflammation and bone resorption in an ex vivo model. Arthritis Rheum 2001;44:1293-303.
- Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappant L, et al. Human interleukin-17: a T-cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 1999;42:963-70.
- O'Gradaigh, Ireland, Bord, et al www.annrheumdis.com on June 18, 2023 by guest. Protected by copyright. http://ard.bmj.com/ Ann Rheum Dis: first published as 10.1136/ard.2003.008458 on 12 March 2004. Downloaded from
Cited by
Sorted by citations
Kearns, A. E., Khosla, S., & Kostenuik, P. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0014 · Cited by 824 · see citing works
PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2
Mao, D., Epple, H., Uthgenannt, B., Novack, D. V., & Faccio, R. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28775 · Cited by 214 · see citing works
Cross-Presentation by Osteoclasts Induces FoxP3 in CD8+ T Cells
Kiesel, J. R., Buchwald, Z. S., & Aurora, R. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803897 · Cited by 109 · see citing works
- Authors
- O' Gradaigh, D., Ireland, D., Bord, S., & Compston, J. E.
- Affiliations
- University of Cambridge (GB)
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 63
- Issue
- 4
- Pages
- 354-359
- ISSN
- 0003-4967 (ISSN-L)
- PMC
- PMC1754946
- OpenAlex
- W2030077822
- Cited by
- 111
- References
- 36
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 9 · 2014: 10 · 2013: 5 · 2012: 9
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- University of Cambridge
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- rheumatoid arthritis, joint erosions, osteoclastogenesis, osteoclasts, RANKL, TNF-α, IL-1β, osteoprotegerin, interleukin-1 receptor antagonist, bone resorption, CD14+ monocytes
- MeSH terms
- Arthritis, Rheumatoid, Bone Resorption, Cell Division, Cells, Cultured, Flow Cytometry, Glycoproteins, Humans, Interleukin-1, Joints, Lymphocytes, Osteoclasts, Time Factors, Tumor Necrosis Factor-alpha, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Lipopolysaccharide Receptors, Osteoprotegerin
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