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Osteoclast differentiation and activation
Abstract
Osteoclasts are specialized cells derived from the monocyte/macrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. Discovery of the RANK signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Further study of this pathway is providing the molecular basis for developing therapeutics to treat osteoporosis and other diseases of bone loss.
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“Because TRAIL and RANKL are known to regulate osteoclast differentiation and survival (33–35), these findings suggest that increased RANK (tumor necrosis factor receptor superfamily member 11a) signaling may be involved in the regulation of bone growth and remodeling induced by ACVR2B/Fc.”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [33]
In the citing paper
“Because TRAIL and RANKL are known to regulate osteoclast differentiation and survival (33–35), these findings suggest that increased RANK (tumor necrosis factor receptor superfamily member 11a) signaling may be involved in the regulation of bone growth and remodeling induced by ACVR2B/Fc.”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [33]
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BackgroundMócsai, A., Humphrey, M. B., Ziffle, J. V., Hu, Y., Burghardt, A. J., Spusta, S. C., Majumdar, S., Lanier, L. L., Lowell, C. A., & Nakamura, M. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401602101 · Cited by 467
Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads
Doherty, T. M., Asotra, K., Fitzpatrick, L. A., Qiao, J.-H., Wilkin, D. J., Detrano, R., Dunstan, C. R., Shah, P. K., & Rajavashisth, T. B. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1932554100 · Cited by 465
The role of NFAT in osteoclast formation
TAKAYANAGI, H. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1402.071 · Cited by 442
Kim, K., Lee, S., Kim, J. H., Choi, Y., & Kim, N. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0237 · Cited by 448
Tumor necrosis factor-α: molecular and cellular mechanisms in skeletal pathology
Nanes, M. S. (2003) · Gene · doi:10.1016/s0378-1119(03)00841-2 · Cited by 440
Orthodontic tooth movement: The biology and clinical implications
Li, Y., Jacox, L. A., Little, S. H., & Ko, C. (2018) · The Kaohsiung Journal of Medical Sciences · doi:10.1016/j.kjms.2018.01.007 · Cited by 439
“RANKL is expressed on osteoblasts, and it promotes osteoclast differentiation by binding to RANK on osteoclast precursors [5,6].”
BackgroundOsteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
McDonald, M. M., Khoo, W. H., Ng, P. Y., Xiao, Y., Zamerli, J., Thatcher, P., Kyaw, W., Pathmanandavel, K., Grootveld, A. K., Moran, I., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.002 · Cited by 433
“Osteoclasts are specialized cells formed by the fusion of committed monocyte/macrophage hematopoietic lineage precursor cells (Boyle et al., 2003; Ikeda and Takeshita, 2016).”
Macrophages and lipid metabolism
Remmerie, A., & Scott, C. L. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.01.020 · Cited by 451
“termed osteoclasts, are specialised in bone resorption [20] and microglia in the brain function in the synaptic ‘pruning’ crucial in the development and maintenance of the central nervous system [21].”
BackgroundBone Quality: The Determinants of Bone Strength and Fragility
Fonseca, H., Moreira‐Gonçalves, D., Coriolano, H.-J. A., & Duarte, J. A. (2013) · Sports Medicine · doi:10.1007/s40279-013-0100-7 · Cited by 456
“increases in receptor activator of nuclear factor kappa-B ligand (RANK-L) [160, 161] and macrophage colonystimulating factor (M-CSF) secretion [157], as well as formation of apoptotic bodies [162], are involved in osteoclast activation.”
BackgroundPreshaw, P. M., & Taylor, J. J. (2011) · Journal Of Clinical Periodontology · doi:10.1111/j.1600-051x.2010.01671.x · Cited by 438
Bone physiology as inspiration for tissue regenerative therapies
Lopes, D., Martins‐Cruz, C., Oliveira, M. B., & Mano, J. F. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.09.028 · Cited by 458
Mechanistic insight into osteoclast differentiation in osteoimmunology
Takayanagi, H. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-004-0612-6 · Cited by 413
“Based on the fact that the addition of RANKL and M-CSF can induce osteoclast differentiation in culture, it has been generally believed that RANKL and M-CSF are not only essential but also sufficient for osteoclastogenesis [24].”
BackgroundCoordination of PGC-1β and iron uptake in mitochondrial biogenesis and osteoclast activation
Ishii, K.-A., Fumoto, T., Iwai, K., Takeshita, S., Ito, M., Shimohata, N., Aburatani, H., Taketani, S., Lelliott, C. J., Vidal-Puig, A., et al. (2009) · Nature Medicine · doi:10.1038/nm.1910 · Cited by 410
“It is widely accepted that bone marrow macrophages (BMMs) differentiate into tartrate-resistant acid phosphatase (TRAP)–positive pre-osteoclasts, which then fuse with each other and become multinucleated mature osteoclasts under the stimulation of two essential cytokines, macrophage colony–stimulating factor (M-CSF) a…”
BackgroundThe Significance of Vasoactive Intestinal Peptide in Immunomodulation
Delgado, M., Pozo, D., & Ganea, D. (2004) · Pharmacological Reviews · doi:10.1124/pr.56.2.7 · Cited by 415
“Osteoclasts are multinucleated giant cells originated by fusion of mononuclear cells from hematopoietic precursors closely related to monocytes/macrophages (Teitelbaum, 2000; Boyle et al., 2003).”
BackgroundYamashita, T., Yao, Z., Li, F., Zhang, Q., Badell, I. R., Schwarz, E. M., Takeshita, S., Wagner, E. F., Noda, M., Matsuo, K., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610701200 · Cited by 414
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“At present, the drug treatments for osteoporosis, including estrogens, bisphosphonates, and selective estrogen-receptor modulators, target OC-mediated bone resorption, chiefly retarding BMD loss and thereby decreasing the risk of bone fractures (22, 24).”
BackgroundChemokines in Oral Inflammatory Diseases: Apical Periodontitis and Periodontal Disease
Silva, T. A., Garlet, G. P., Fukada, S. Y., Silva, J. S., & Cunha, F. Q. (2007) · Journal of Dental Research · doi:10.1177/154405910708600403 · Cited by 405
“However, although the differentiation of osteoclasts can be achieved by chemokine-chemokine receptor interaction, their activation seems to be dependent on RANKL (Wright et al., 2005; Kim et al., 2006b).”
BackgroundInfluentialOsteoclasts: more than ‘bone eaters’
Charles, J. F., & Aliprantis, A. O. (2014) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.06.001 · Cited by 391
Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases
Callaway, D. A., & Jiang, J. X. (2015) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-015-0656-4 · Cited by 393
Ca 2+ ‐NFATc1 signaling is an essential axis of osteoclast differentiation
Negishi‐Koga, T., & Takayanagi, H. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00821.x · Cited by 415
“Osteoclasts actively degrade the bone matrix proteins and decalcify the inorganic components of bone by releasing proteolytic enzymes such as cathepsin K and matrix metalloproteinase (MMP) and large amounts of hydrochloric acid, respectively (1).”
BackgroundInfluentialOsteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche
Lawson, M. A., McDonald, M. M., Kovačić, N., Khoo, W. H., Terry, R. L., Down, J. M., Kaplan, W. H., Paton‐Hough, J., Fellows, C., Pettitt, J. A., et al. (2015) · Nature Communications · doi:10.1038/ncomms9983 · Cited by 389
Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption
Kitaura, H., Marahleh, A., Ohori, F., Noguchi, T., Shen, W.-R., Qi, J., Nara, Y., Pramusita, A., Kinjo, R., & Mizoguchi, I. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21145169 · Cited by 405
“However, OPG, which is a RANKL decoy receptor, prevents RANKL-RANK binding [74].”
BackgroundBao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 402
The Cellular and Molecular Biology of Periprosthetic Osteolysis
Purdue, P. E., Koulouvaris, P., Potter, H. G., Nestor, B. J., & Sculco, T. P. (2006) · Clinical Orthopaedics and Related Research · doi:10.1097/01.blo.0000238813.95035.1b · Cited by 372
“lineage, and represent the only cell type capable of bone resorption.(13) When considering the causes of excessive bone resorption”
BackgroundOsteoclast differentiation independent of the TRANCE–RANK–TRAF6 axis
Kim, N., Kadono, Y., Takami, M., Lee, J., Lee, S.-H., Okada, F., Kim, J. H., Kobayashi, T., Odgren, P. R., Nakano, H., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050978 · Cited by 374
“Collectively, it has been proposed that TRANCE–RANK interaction and subsequent signaling via TRAF6 are essential for the differentiation of mature osteoclasts (1, 2, 4).”
BackgroundTissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Guan, F., Wang, R., Yi, Z., Luo, P., Liu, W., Xie, Y., Liu, Z., Xia, Z., Zhang, H., & Cheng, Q. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02124-y · Cited by 371
Jeffcoate, W. J., Game, F. L., & Cavanagh, P. R. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67029-8 · Cited by 369
Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading
You, L., Temiyasathit, S., Lee, P., Kim, C. H., Tummala, P., Yao, W., Kingery, W. S., Malone, A. M. D., Kwon, R. Y., & Jacobs, C. R. (2007) · Bone · doi:10.1016/j.bone.2007.09.047 · Cited by 361
“* p 0.05 DISCUSSION: In this project we have demonstrated that mechanical stimulation experienced by osteocytes has an anti-resorptive effect on the RANKL/OPG signaling axis.”
BackgroundInfluentialThe role of the EGFR signaling in tumor microenvironment
Luca, A. D., Carotenuto, A., Rachiglio, A. M., Gallo, M., Maiello, M. R., Aldinucci, D., Pinto, A., & Normanno, N. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21260 · Cited by 369
“Osteoclasts are the specialized progeny of hemopoietic precursors committed to the monocyte/macrophage lineage that, upon appropriate stimuli, fuse by giving rise to mature bone resorbing cells (Boyle et al., 2003).”
BackgroundInfluential
Metadata
- Authors
- Boyle, W. J., Simonet, W. S., & Lacey, D. L.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Boyle, William J.
- ORCID
- Boyle, William J.
- Venue
- Nature
- Published
- 2003-05
- Volume
- 423
- Issue
- 6937
- Pages
- 337-342
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2093252878
- Cited by
- 6,670
- References
- 77
- Citations by year
- 2026: 240 · 2025: 269 · 2024: 294 · 2023: 357 · 2022: 349 · 2021: 404 · 2020: 376 · 2019: 381 · 2018: 371 · 2017: 324 · 2016: 311 · 2015: 332 · 2014: 352 · 2013: 315 · 2012: 336
- FWCI
- 11.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Bone and Dental Protein Studies
- Keywords
- osteoclasts, osteoclastogenesis, bone resorption, monocyte/macrophage lineage, bone matrix degradation, hormonal regulation of bone, osteoporosis
- MeSH terms
- Animals, Bone Resorption, Carrier Proteins, Cell Differentiation, Glycoproteins, Humans, Membrane Glycoproteins, Osteoclasts, Osteoporosis, Signal Transduction, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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