Continuous RANKL Inhibition in Osteoprotegerin Transgenic Mice and Rats Suppresses Bone Resorption without Impairing Lymphorganogenesis or Functional Immune Responses
Open accessAbstract
Receptor activator of NF-κB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The effects of RANKL are inhibited by a soluble decoy receptor called osteoprotegerin (OPG). Total ablation of RANKL in knockout mice leads to high bone mass, lymph node agenesis, and altered lymphocyte differentiation. In contrast, RANKL inhibition via OPG suppresses bone resorption but not inflammation in animal models of inflammatory bone loss. This suggests that the immune phenotype of RANKL knockout mice is related to total RANKL ablation. We hypothesized that prenatal RANKL inhibition via OPG overexpression would suppress bone resorption without influencing lymph node formation or subsequent immune responses. Transgenic rats were created, wherein soluble OPG was overexpressed by 100-fold vs wild type (WT) controls, by gestational day 11 (i.e., before lymph node formation). The structure of lymph nodes, spleen, and thymus of OPG-transgenic (OPG-Tg) animals were comparable to those of age-matched WT rats at gestational day 19 and in adulthood. The OPG-Tg neonates had elevated bone mass, confirming the prenatal inhibition of RANKL. Adult OPG-Tg rats and OPG-Tg mice exhibited no significant functional alterations relative to WT controls when subjected to immune challenges to test for altered innate and humoral responses (e.g., contact hypersensitivity to oxazolone, IgM response to Pneumovax, IgG response to keyhole limpet hemocyanin, or cytokine response to LPS). In summary, prenatal RANKL inhibition did not impair lymph node development, nor did continuous life-long RANKL inhibition cause obvious changes in innate or humoral immune responses in mice or rats.
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Prenatal RANKL inhibition in OPG transgenic mice and rats did not cause observed changes in lymph node development or architecture.
“prenatal inhibition of RANKL in OPG transgenic mice and rats did not lead to any observed changes in lymph node development or architecture (4,182).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [182]
OPG is overexpressed 100-fold during gestation and throughout life in these animals, associated with marked bone turnover suppression.
“OPG is overexpressed in these animals by 100-fold during gestation and throughout life, and this level of OPG was associated with marked suppression of bone turnover (169, 182).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [182]
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Cites
Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
Lacey, D. L., Timms, E., Tan, H.-L., Kelley, M. J., Dunstan, C. R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81569-x · Cited by 5,439 · see citing works
Self-citationOsteoprotegerin: a novel secreted protein involved in the regulation of bone density.
Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M.-S., Lüthy, R., Nguyen, H. Q., Wooden, S., Bennett, L., Boone, T., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80209-3 · Cited by 5,130 · see citing works
Self-citationOPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis.
Kong, Y.-Y., Yoshida, H., Sarosi, I., Tan, H.-L., Timms, E., Capparelli, C., Morony, S., Oliveira-dos-Santos, A. J., Van, G., Itie, A., et al. (1999) · Nature · doi:10.1038/16852 · Cited by 3,351 · see citing works
Self-citationA homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function.
Anderson, D. M., Maraskovsky, E., Billingsley, W. L., Dougall, W. C., Tometsko, M. E., Roux, E. R., Teepe, M. C., DuBose, R. F., Cosman, D., & Galibert, L. (1997) · Nature · doi:10.1038/36593 · Cited by 2,290 · 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
Self-citationRANK is essential for osteoclast and lymph node development.
Dougall, W. C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M. E., Maliszewski, C. R., et al. (1999) · Genes & Development · doi:10.1101/gad.13.18.2412 · Cited by 1,478 · see citing works
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 · see citing works
Self-citationWong, B. R., Josien, R., Lee, S. Y., Sauter, B., Li, H.-L., Steinman, R. M., & Choi, Y. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.12.2075 · Cited by 853 · 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
Fata, J. E., Kong, Y.-Y., Li, J., Sasaki, T., Irie-Sasaki, J., Moorehead, R. A., Elliott, R., Scully, S., Voura, E. B., Lacey, D. L., et al. (2000) · Cell · doi:10.1016/s0092-8674(00)00103-3 · Cited by 756 · see citing works
Organogenesis of lymphoid tissues
Mebius, R. E. (2003) · Nature reviews. Immunology · doi:10.1038/nri1054 · Cited by 747 · see citing works
Min, H., Morony, S., Sarosi, I., Dunstan, C. R., Capparelli, C., Scully, S., Van, G., Kaufman, S., Kostenuik, P. J., Lacey, D. L., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.4.463 · Cited by 550 · see citing works
Self-citationOsteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo.
Lacey, D. L., Tan, H. L., Lu, J., Kaufman, S., Van, G., Qiu, W., Rattan, A., Scully, S., Fletcher, F., Juan, T., et al. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64556-7 · Cited by 391 · see citing works
Self-citationOsteoprotegerin Reduces Osteoclast Numbers and Prevents Bone Erosion in Collagen-Induced Arthritis
Romas, E., Sims, N. A., Hards, D. K., Lindsay, M., Quinn, J. W. M., Ryan, P. F. J., Dunstan, C. R., Martin, T. J., & Gillespie, M. T. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64417-3 · Cited by 368 · see citing works
Zwerina, J., Hayer, S., Tohidast-Akrad, M., Bergmeister, H., Redlich, K., Feige, U., Dunstan, C. R., Kollias, G., Steiner, G. E., Smolen, J. S., et al. (2004) · Arthritis & Rheumatism · doi:10.1002/art.11487 · Cited by 308 · see citing works
Yun, T. J., Chaudhary, P. M., Shu, G. L., Frazer, J. K., Ewings, M. K., Schwartz, S. M., Pascual, V., Hood, L. E., & Clark3, E. A. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.11.6113 · Cited by 307 · see citing works
Redlich, K., Hayer, S., Maier, A., Dunstan, C. R., Tohidast‐Akrad, M., Lang, S., Türk, B., Pietschmann, P., Woloszczuk, W., Haralambous, S., et al. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10097 · Cited by 285 · see citing works
Regulation of Peripheral Lymph Node Genesis by the Tumor Necrosis Factor Family Member Trance
Kim, D., Mebius, R. E., MacMicking, J. D., Jung, S., Cupedo, T., Castellanos, Y. P., Rho, J., Wong, B. R., Josien, R., Kim, N., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.10.1467 · Cited by 264 · see citing works
Bachmann, M. F., Wong, B. R., Josien, R., Steinman, R. M., Oxenius, A., & Choi, Y. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.189.7.1025 · Cited by 260 · see citing works
Ashcroft, A. J., Cruickshank, S. M., Croucher, P. I., Perry, M. J., Rollinson, S. J., Lippitt, J. M., Child, J. A., Dunstan, C. R., Felsburg, P. J., Morgan, G. J., et al. (2003) · Immunity · doi:10.1016/s1074-7613(03)00326-1 · Cited by 177 · see citing works
Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice.
Schett, G., Redlich, K., Hayer, S., Zwerina, J., Bolon, B., Dunstan, C., Görtz, B., Schulz, A., Bergmeister, H., Kollias, G., et al. (2003) · Arthritis & Rheumatism · doi:10.1002/art.11150 · Cited by 150 · see citing works
Self-citationMizuno, A., Kanno, T., HOSHI, M., Shibata, O., Yano, K., Fujise, N., Kinosaki, M., Yamaguchi, K., Tsuda, E., Murakami, A., et al. (2002) · Journal of Bone and Mineral Metabolism · doi:10.1007/s007740200049 · Cited by 146 · see citing works
Maruyama, K., Takada, Y., Ray, N., Kishimoto, Y., Penninger, J. M., Yasuda, H., & Matsuo, K. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.3799 · Cited by 105 · see citing works
Capparelli, C., Morony, S., Warmington, K., Adamu, S., Lacey, D., Dunstan, C. R., Stouch, B., Martin, S., & Kostenuik, P. J. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.5.852 · Cited by 103 · see citing works
Self-citationStolina, M., Adamu, S., Ominsky, M., Dwyer, D., Asuncion, F., Geng, Z., Middleton, S., Brown, H., Pretorius, J., Schett, G., et al. (2005) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.050601 · Cited by 99 · see citing works
Self-citationCampagnuolo, G., Bolon, B., & Feige, U. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10369 · Cited by 78 · see citing works
Self-citationByrne, F. R., Morony, S., Warmington, K., Geng, Z., Brown, H. L., Flores, S. A., Fiorino, M., Yin, S. L., Hill, D., Porkess, V., et al. (2004) · Gut · doi:10.1136/gut.2003.035113 · Cited by 65 · see citing works
Self-citationSenaldi, G., Stolina, M., Guo, J., Faggioni, R., McCabe, S., Kaufman, S. A., Van, G. Y., Xu, W., Fletcher, F. A., Boone, T. C., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.11.5690 · Cited by 54 · see citing works
Self-citationFrolik, C. A., Cain, R. L., Sato, M., et al. (1999) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.1999.14.2.163 · Cited by 45 · see citing works
Padigel, U. M., Kim, N., Choi, Y., & Farrell, J. P. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.10.5437 · Cited by 36 · see citing works
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Kearns, A. E., Khosla, S., & Kostenuik, P. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0014 · Cited by 824 · see citing works
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- Authors
- Stolina, M., Dwyer, D., Ominsky, M. S., Corbin, T., Van, G., Bolon, B., Sarosi, I., McCabe, J., Zack, D. J., & Kostenuik, P.
- Affiliations
- Amgen (United States) (US)
- GEMpath Inc. , Cedar City, UT 84720
- Corresponding author
- Stolina, Marina
- Dwyer, Denise
- Kostenuik, Paul
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-12-01
- Volume
- 179
- Issue
- 11
- Pages
- 7497-7505
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2153522850
- Cited by
- 63
- References
- 30
- Citations by year
- 2026: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 6 · 2014: 2 · 2013: 4 · 2012: 6
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- RANKL, osteoprotegerin, bone resorption, osteoclasts, lymph node development, immune response, transgenic rats, transgenic mice, bone mass, innate immunity, humoral immunity, contact hypersensitivity, IgM antibody response, IgG antibody response
- MeSH terms
- Animals, Bone Resorption, Disease Models, Animal, Immunity, Lipopolysaccharides, Lymph Nodes, Lymphocytes, Mice, Inbred Strains, Mice, Transgenic, Phenotype, Rats, Sprague-Dawley, Mice, Knockout, Mice, Rats, Osteoprotegerin, RANK Ligand
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