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The RANKL/RANK/OPG pathway
Abstract
Understanding of osteoclast formation and activation has advanced considerably since the discovery of the RANKL/RANK/OPG system in the mid 1990s. Osteoblasts and stromal stem cells express receptor activator of NF-jB ligand (RANKL), which binds to its receptor, RANK, on the surface of osteoclasts and their precursors. This regulates the differentiation of precursors into multinucleated osteoclasts and osteoclast activation and survival both normally and in most pathologic conditions associated with increased bone resorption. Osteoprotegerin (OPG) is secreted by osteoblasts and osteogenic stromal stem cells and protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from interacting with RANK. The RANKL/OPG ratio in bone marrow is thus an important determinant of bone mass in normal and disease states. RANKL/RANK signaling also regulates lymph node formation and mammary gland lactational hyperplasia in mice, and OPG protects large arteries of mice from medial calcification. This article reviews the roles of the RANKL/RANK/OPG system in bone and other tissues.
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“It has been shown that the receptor activator of nuclear factor-kappa B ligand (RANKL)-RANK-osteoprotegerin (OPG) (RANKL-RANK-OPG) pathway exerts a crucial role in osteoclast differentiation and bone resorption [87,88,89].”
From An Overlooked Bone Metabolic Disorder: Cigarette Smoking-Induced Osteoporosis (2022) · cites this paper as [87]
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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
Osteoprotegerin: 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
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
Nakashima, K., Zhou, X., Kunkel, G., Zhang, Z., Deng, J. M., Behringer, R. R., & de Crombrugghe, B. (2002) · Cell · doi:10.1016/s0092-8674(01)00622-5 · Cited by 3,608
Takayanagi, H., Kim, S., Koga, T., Nishina, H., Isshiki, M., Yoshida, H., Saiura, A., Isobe, M., Yokochi, T., Inoue, J.-I., et al. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00369-6 · Cited by 2,701
Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.
Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., Capparelli, C., Scully, S., Tan, H. L., Xu, W., Lacey, D. L., et al. (1998) · Genes & Development · doi:10.1101/gad.12.9.1260 · Cited by 2,483
A 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
Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems
Takayanagi, H. (2007) · Nature Reviews Immunology · doi:10.1038/nri2062 · Cited by 1,878
Genetic regulation of osteoclast development and function
Teitelbaum, S. L., & Ross, F. P. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1122 · Cited by 1,720
T-Cell mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ.
Takayanagi, H., Ogasawara, K., Hida, S., Chiba, T., Murata, S., Sato, K., Takaoka, A., Yokochi, T., Oda, H., Tanaka, K., et al. (2000) · Nature · doi:10.1038/35046102 · Cited by 1,358
TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signalingPreprint
Lomaga, M. A., Yeh, W., Sarosi, I., Duncan, G. S., Furlonger, C. L., Ho, A. P., Morony, S., Capparelli, C., Van, G. Y., Kaufman, S., et al. (1999) · Genes & Development · doi:10.1101/gad.13.8.1015 · Cited by 1,265
RANKL–RANK signaling in osteoclastogenesis and bone disease
Wada, T., Nakashima, T., Nishina, H., & Penninger, J. M. (2005) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2005.11.007 · Cited by 1,230
Yasuda, H., Shima, N., Nakagawa, N., Mochizuki, S.-I., Yano, K., Fujise, N., Sato, Y., Goto, M., Yamaguchi, K., Kuriyama, M., et al. (1998) · Endocrinology · doi:10.1210/endo.139.3.5837 · Cited by 1,201
Black, D. M., Greenspan, S. L., Ensrud, K. E., Palermo, L., McGowan, J., Lang, T., Garnero, P., Bouxsein, M., Bilezikian, J. P., & Rosen, C. J. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa031975 · Cited by 1,168
Wong, B. R., Rho, J., Arron, J. R., Robinson, E. A., Orlinick, J. R., Chao, M. V., Kalachikov, S. M., Cayani, E., Bartlett, F. S., Frankel, W. N., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.40.25190 · Cited by 1,042
Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases
Hofbauer, L. C. (2004) · JAMA · doi:10.1001/jama.292.4.490 · Cited by 990
Role of osteoblasts in hormonal control of bone resorption—A hypothesis
Rodan, G. A., & Martin, T. J. (1981) · Calcified Tissue International · doi:10.1007/bf02409454 · Cited by 982
Autoamplification of NFATc1 expression determines its essential role in bone homeostasis
Asagiri, M., Sato, K., Usami, T., Ochi, S., Nishina, H., Yoshida, H., Morita, I., Wagner, E. F., Mak, T. W., Serfling, E., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20051150 · Cited by 849
Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis
Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., et al. (2004) · Nature · doi:10.1038/nature02444 · Cited by 832
Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis
Zhao, C., Irie, N., Takada, Y., Shimoda, K., Miyamoto, T., Nishiwaki, T., Suda, T., & Matsuo, K. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.012 · Cited by 777
Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells
Kollet, Ó., Dar, A., Shivtiel, S., Kalinkovich, A., Lapid, K., Sztainberg, Y., Tesio, M., Samstein, R. M., Goichberg, P., Spiegel, A., et al. (2006) · Nature Medicine · doi:10.1038/nm1417 · Cited by 774
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
RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β
Takayanagi, H., Kim, S., Matsuo, K., Suzuki, H. I., Suzuki, T., Sato, K., Yokochi, T., Oda, H., Nakamura, K., Ida, N., et al. (2002) · Nature · doi:10.1038/416744a · Cited by 719
Osteoclast-derived activity in the coupling of bone formation to resorption
Martin, T. J., & Sims, N. A. (2005) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.12.004 · Cited by 661
Naito, A., Azuma, S., Tanaka, S., Miyazaki, T., Takaki, S., Takatsu, K., Nakao, K., Nakamura, K., Katsuki, M., Yamamoto, T. S., et al. (1999) · Genes to Cells · doi:10.1046/j.1365-2443.1999.00265.x · Cited by 626
TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases
Feldmann, M., & Maini, R. N. (2003) · Nature Medicine · doi:10.1038/nm939 · Cited by 586
Lee, S.-H., Rho, J., Jeong, D., Sul, J., Kim, T. S., Kim, N., Kang, J.-S., Miyamoto, T. K., Suda, T., Lee, S., et al. (2006) · Nature Medicine · doi:10.1038/nm1514 · Cited by 547
NFAT and Osterix cooperatively regulate bone formation
Koga, T., Matsui, Y., Asagiri, M., Kodama, T., Crombrugghe, B. D., Nakashima, K., & Takayanagi, H. (2005) · Nature Medicine · doi:10.1038/nm1270 · Cited by 497
Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis
Hughes, A. E., Ralston, S. H., Marken, J., Bell, C., Macpherson, H. K., Wallace, R. G. H., Hul, W. V., Whyte, M. P., Nakatsuka, K., Hovy, L., et al. (2000) · Nature Genetics · doi:10.1038/71667 · Cited by 484
Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin
Collin‐Osdoby, P. (2004) · Circulation Research · doi:10.1161/01.res.0000149165.99974.12 · Cited by 474
Osteoprotegerin Deficiency and Juvenile Paget's Disease
Whyte, M. P., Obrecht, S. E., Finnegan, P. M., Jones, J. L., Podgornik, M. N., McAlister, W. H., & Mumm, S. R. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa013096 · Cited by 446
Mechanistic insight into osteoclast differentiation in osteoimmunology
Takayanagi, H. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-004-0612-6 · Cited by 413
MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL
Lynch, C. C., Hikosaka, A., Acuff, H. B., Martin, M. D., Kawai, N., Singh, R. K., Vargo-Gogola, T. C., Begtrup, J. L., Peterson, T. E., Fingleton, B., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.013 · Cited by 402
Bennett, B. J., Scatena, M., Kirk, E. A., Rattazzi, M., Varon, R. M., Averill, M., Schwartz, S. M., Giachelli, C. M., & Rosenfeld, M. E. (2006) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000236428.91125.e6 · Cited by 304 · cited 1×
“Although this observation suggests that OPG may protect against calcification of atherosclerosis [ 36 ], it remains to be determined whether OPG or RANKL signaling play important roles in cardiovascular disease.”
BackgroundChen, G., Sircar, K., Aprikian, A. G., Potti, A., Goltzman, D., & Rabbani, S. A. (2006) · Cancer · doi:10.1002/cncr.21978 · Cited by 229
Cundy, T. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.18.2119 · Cited by 228
Ikeda, T., Kasai, M., Utsuyama, M., & Hirokawa, K. (2001) · Endocrinology · doi:10.1210/endo.142.4.8070 · Cited by 215
Rogers, A., & Eastell, R. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0794 · Cited by 215
Li, P., Schwarz, E. M., O’Keefe, R. J., Ma, L., Looney, R. J., Ritchlin, C. T., Boyce, B. F., & Xing, L. (2004) · Arthritis & Rheumatism · doi:10.1002/art.11419 · Cited by 208
Self-citationYao, Z., Li, P., Zhang, Q., Schwarz, E. M., Keng, P., Arbini, A., Boyce, B. F., & Xing, L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512624200 · Cited by 197
Self-citationMechanisms of Disease: the link between RANKL and arthritic bone disease
Schett, G. A., Hayer, S., Zwerina, J., Redlich, K., & Smolen, J. S. (2005) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0036 · Cited by 189
Cyclosporine induces high bone turnover and may contribute to bone loss after heart transplantation
ÉBAUD, D. T., Krieg, M., Berguer, D. G., Jacquet, A. F., Goy, J., & BURCKHARDT, P. (1996) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.1996.00170.x · Cited by 154
Kurihara, N., Hiruma, Y., Zhou, H., Subler, M. A., Dempster, D. W., Singer, F. R., Reddy, S. V., Gruber, H. E., Windle, J. J., & Roodman, G. D. (2007) · Journal of Clinical Investigation · doi:10.1172/jci28267 · Cited by 127
Receptor Activator of NF-κB Ligand Regulates the Proliferation of Mammary Epithelial Cells via Id2
Kim, N., Kim, H.-J., Koo, B., Kwon, M.-C., Kim, Y.-W., Cho, Y., Yokota, Y., Penninger, J. M., & Kong, Y. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.3.1002-1013.2006 · Cited by 110
Ma, Y. L., Bryant, H. U., Zeng, Q., Schmidt, A., Hoover, J. L., Cole, H. W., Yao, W., Jee, W. S. S., & Sato, M. (2003) · Endocrinology · doi:10.1210/en.2002-221061 · Cited by 91
Embryonic Heart Failure in NFATc1 −/− Mice
Phoon, C. K. L., Ji, R. P., Aristizábal, O., Worrad, D. M., Zhou, B., Baldwin, H. S., & Turnbull, D. H. (2004) · Circulation Research · doi:10.1161/01.res.0000133681.99617.28 · Cited by 91
Osteoprotegerin, the bone protector, is a surprising target for β-catenin signaling
Boyce, B. F., Xing, L., & Chen, D. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.11.011 · Cited by 54
Self-citationMalignant Autosomal Recessive Osteopetrosis Caused by Spontaneous Mutation of Murine Rank
Kapur, R. P., Yao, Z., Iida, M. H., Clarke, C. M., Doggett, B., Xing, L., & Boyce, B. F. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040713 · Cited by 39
Self-citation
Research works printed but not linked: 2
- American Society for Bone and Mineral Research President’s Committee on Nomenclature: Proposed standard nomenclature for new tumor necrosis factor family members involved in the regulation of bone resorption. The American Society for Bone and Mineral Research President’s Committee on Nomenclature. J Bone Miner Res 2000, 15:2293–2296.
- Yao Z, Matsuo K, Nishimura R, et al.: c-Fos/NFAT1-or 2-mediated osteoclastogenesis requires NF-κB p50/p52 expression [abstract]. J Bone Miner Res 2005, 20(suppl 1):S145.
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Metadata
- Authors
- Boyce, B. F., & Xing, L.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Boyce, Brendan F.
- Venue
- Current Osteoporosis Reports
- Published
- 2007-09
- Volume
- 5
- Issue
- 3
- Pages
- 98-104
- ISSN
- 1544-1873 (ISSN-L)
- 1544-2241
- OpenAlex
- W2055590859
- Cited by
- 339
- References
- 48
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 32 · 2023: 29 · 2022: 30 · 2021: 26 · 2020: 31 · 2019: 21 · 2018: 24 · 2017: 25 · 2016: 20 · 2015: 17 · 2014: 4 · 2013: 8 · 2012: 5
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Current Osteoporosis Reports (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- RANK/RANKL/OPG pathway, osteoclastogenesis, osteoclast activation, bone resorption, osteoblasts, stromal stem cells, RANKL/OPG ratio, bone mass regulation, vascular calcification, NF-κB signaling
- MeSH terms
- Humans, Osteoclasts, Osteoporosis, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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