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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Increased RANK signaling may be involved in the regulation of bone growth and remodeling induced by ACVR2B/Fc.
“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]
TRAIL and RANKL are known to regulate osteoclast differentiation and survival.
“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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“Of these cytokines, tumor necrosis factor- and interleukin1 and -6, produced primarily by stimulated macrophages, play crucial roles in the pathogenesis of rheumatoid arthritis and osteoarthrosis, with respect to the acceleration and progression of cartilage degradation, because they promote bone resorption through th…”
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“However, with some exceptions (Boyle et al., 2003), these signals remain largely unknown.”
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“Osteoclasts are large multinucleated cells of hematopoietic origin formed by the differentiation and fusion of mononuclear monocyte-macrophage lineage precursors after stimulation by receptor activation of nuclear factor κ B-ligands (RANKL) and macrophage colony-stimulating factors (M-CSF) [8,22,42].”
BackgroundInfluentialCostimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis
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BackgroundRandomized Trial of Short- Versus Long-Course Radiotherapy for Palliation of Painful Bone Metastases
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“M-CSF and RANKL are expressed by bone marrow stromal cells as well as by periosteal and endosteal OBs in response to hormones and cytokines stimulating bone resorption.((13)) Tumor necrosis factor (TNF) is an inflammatory cytokine produced by myeloid cells that promotes osteoclastogenesis.”
BackgroundOsteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells
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“OCLs are derived from hematopoietic stem cells and require RANKL signals from osteoblasts for their proliferation, differentiation and bone-resorbing activit”
BackgroundFunctional plasticity of macrophages: reversible adaptation to changing microenvironments
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BackgroundThe aging of Wolff’s “law”: Ontogeny and responses to mechanical loading in cortical bone
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“Stimulators include PTH, 1,25(OH)2 vitamin D3, thyroid hormone, glucocorticoids, IGF-I, and BMP-2 and -4; inhibitors include calcitonin, nitric oxide (NO), gonadal steroids, and interleukin-1 and -6 (Jee, 2001; Boyle et al., 2003).”
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OSTEOIMMUNOLOGY: Interplay Between the Immune System and Bone Metabolism
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“Many well-known osteotropic factors, including IL-1, IL-6, and IL-11, are now believed to exert most of their osteoclastogenic activity by inducing TRANCE expression on OBs (60, 64).”
BackgroundInflammation and Bone Loss in Periodontal Disease
Cochran, D. L. (2008) · Journal of Periodontology · doi:10.1902/jop.2008.080233 · Cited by 732 · see citing works
Macrophage diversity in renal injury and repair
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“In vitro, the combination of RANKL andM-CSF is required for optimal osteoclast survival [17].”
BackgroundTransforming Growth Factor-β1 to the Bone
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“Runx2 binding sites are found in the promoters of several bone formation markers including collagen 1, ALP, osteopontin, RANKL, and osteocalcin (149).”
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“Podosomes facilitate adhesion to the bone surface and formation of a sealing zone provides an isolated acidic microenvironment within which the osteoclast can dissolve mineral and digest the bone matrix.(23) Bone mineral is dissolved by secretion of hydrochloric acid and bone matrix is broken down by secretion of prot…”
BackgroundInfluentialBench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab
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Self-citationCurrent Understanding of RANK Signaling in Osteoclast Differentiation and Maturation
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“Osteoclasts are bone-resorbing multinucleated cells that originate from hematopoietic precursors that are formed in the bone marrow (Asagiri and Takayanagi, 2007; Boyle et al., 2003; Karsenty and Wagner, 2002; Teitelbaum, 2000).”
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“Osteoclastogenesis requires signaling cues such as colony-stimulating factor-1 (CSF-1) and receptor activator of nuclear factor-kB ligand (RANKL) [144,145].”
Osteoclast-derived activity in the coupling of bone formation to resorption
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Tissue biology perspective on macrophages
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Osteoblasts in prostate cancer metastasis to bone
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“fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4982">osteoprotegerin , a soluble decoy receptor that inhibits RANK”
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Biology of the RANKL–RANK–OPG System in Immunity, Bone, and Beyond
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“Interestingly, new OCs are generated largely through cell contact-dependent interactions between OC precursors and OBs in the bone stroma (76, 77).”
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“We infer that the susceptibility of macrophages to ZA reflects their lineage relationship to osteoclasts (42, 43), which selectively take up BPs (32, 44).”
BackgroundAdvances in biology of multiple myeloma: clinical applications
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“For example, TRAF6 activates the signaling pathways for NF B and c-Fos (Boyle et al., 2003).”
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“Receptor activator of nuclear factor-kappa B ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival [1].”
BackgroundThe Molecular Clock Mediates Leptin-Regulated Bone Formation
Fu, L., Patel, M. S., Bradley, A., Wagner, E. F., & Karsenty, G. (2005) · Cell · doi:10.1016/j.cell.2005.06.028 · Cited by 575 · see citing works
“The hormone leptin is a regulator of bone remodeling, a homeostatic function maintaining bone mass constant.”
BackgroundRegulation of NFATc1 in Osteoclast Differentiation
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“The multinucleated osteoclasts reorganize the actin cytoskeleton to attach to the bone surface and to resorb the bone.[4] Osteoclast differentiation is regulated by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL).”
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“RANKL expressed by T cells, as well as by osteoblasts and bone marrow stromal cells, triggers signaling in osteoclast precursor cells that elicits the differentiation into their mature form.(8) OPG is expressed ubiquitously by many types of cells and tissues, and it counterregulates”
BackgroundOsteoimmunology: Interactions of the Bone and Immune System
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“kines and hormones, are now believed to exert their primary osteoclastogenic activity by inducing RANKL expression in osteoblast lineage cells (16, 170).”
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“Moreover, the phosphatidyl-inositol-30-kinase (PI3K)/Akt pathways, which involve the mammalian target of rapamycin (mTOR) [110,111], are also targets of TRAF6.”
BackgroundmiR-214 targets ATF4 to inhibit bone formation
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“Osteoclast precursors expressing RANK and CSF1 receptor (encoded by Csf1r ) differentiate into osteoclasts through interaction with osteoblast-lineage cell”
BackgroundPhysiology and diseases of tissue-resident macrophages
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An overview of the regulation of bone remodelling at the cellular level
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“by initiating a cascade of cellular signals resulting in the differentiation and activation of bone-resorbing osteoclast”
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“A persisting inflammatory environment can ultimately disrupt bone homeostasis, which depends on a triad of proteins within the tumor necrosis factor/ tumor necrosis factor-receptor family, consisting of RANKL, its functional receptor (RANK) and its decoy receptor (osteoprotegerin) (17).”
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“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 · see citing works
“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
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“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 435 · see citing works
“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.”
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Bone physiology as inspiration for tissue regenerative therapies
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Mechanistic insight into osteoclast differentiation in osteoimmunology
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“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 · see citing works
“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 412 · see citing works
“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).”
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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 · see citing works
“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 · see citing works
Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases
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Ca <sup>2+</sup> ‐NFATc1 signaling is an essential axis of osteoclast differentiation
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“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 385 · see citing works
Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption
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“However, OPG, which is a RANKL decoy receptor, prevents RANKL-RANK binding [74].”
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The Cellular and Molecular Biology of Periprosthetic Osteolysis
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“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
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“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
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Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading
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“* 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
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“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
- 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
- Health Sciences › Medicine › Rheumatology › 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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