The molecular understanding of osteoclast differentiation
Abstract
Osteoclasts are multinucleated cells of monocyte/macrophage origin that degrade bone matrix. The differentiation of osteoclasts is dependent on a tumor necrosis factor (TNF) family cytokine, receptor activator of nuclear factor (NF)-kappaB ligand (RANKL), as well as macrophage colony-stimulating factor (M-CSF). Congenital lack of osteoclasts causes osteopetrosis, investigation of which has provided insights into the essential molecules for osteoclastogenesis, including TNF receptor-associated factor (TRAF) 6, NF-kappaB and c-Fos. In addition, genome-wide screening techniques have shed light on an additional set of gene products such as nuclear factor of activated T cells (NFAT) c1. Here we summarize the efforts to understand the sequential molecular events induced by RANKL during osteoclast differentiation. RANKL binds to its receptor RANK, which recruits adaptor molecules such as TRAF6. TRAF6 activates NF-kappaB, which is important for the initial induction of NFATc1. NFATc1 is activated by calcium signaling and binds to its own promoter, thus switching on an autoregulatory loop. An activator protein (AP)-1 complex containing c-Fos is required for the autoamplification of NFATc1, enabling the robust induction of NFATc1. Finally, NFATc1 cooperates with other transcriptional partners to activate osteoclast-specific genes. NFATc1 autoregulation is controlled by an epigenetic mechanism, which has profound implications for an understanding of the general mechanism of irreversible…
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NFATc1 binds to its own promoter, switching on an epigenetically controlled autoregulatory cycle that permits efficient induction of TRAP, cathepsin K, DC-STAMP, and ATP6v0d2.
“NFATc1 binds to its own promoter, switching on an epigenetically controlled autoregulatory cycle that permits efficient induction of the osteoclast-specific genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K, as well as the fusion-specific genes, dendritic cell-specific transmembrane protein (DC-STAMP) and ATPase H+ transporting V0 subunit D2 (ATP6v0d2) [20,25,26] (Figure 3).”
From Osteoclasts and Microgravity (2020) · cites this paper as [26]
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- Authors
- Asagiri, M., & Takayanagi, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Takayanagi, Hiroshi
- Venue
- Bone
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 40
- Issue
- 2
- Pages
- 251-264
- ISSN
- 1873-2763 (ISSN-L)
- 8756-3282
- OpenAlex
- W2064346787
- Cited by
- 1,363
- References
- 14
- Citations by year
- 2026: 31 · 2025: 50 · 2024: 63 · 2023: 92 · 2022: 86 · 2021: 86 · 2020: 82 · 2019: 90 · 2018: 97 · 2017: 83 · 2016: 60 · 2015: 97 · 2014: 72 · 2013: 66 · 2012: 68
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bone (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Science and Technology Agency
- Nakatomi Foundation
- Inamori Foundation
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- osteoclastogenesis, RANKL, RANK, TRAF6, NF-κB, NFATc1, c-fos, AP-1, autoregulation, epigenetic regulation, cell fate determination, osteopetrosis, macrophage colony-stimulating factor, bone resorption
- MeSH terms
- Animals, Bone Resorption, Cell Differentiation, Humans, Osteoclasts, Tumor Necrosis Factor-alpha, Signal Transduction, Macrophage Colony-Stimulating Factor, Transcription Factor AP-1, Epigenesis, Genetic, TNF Receptor-Associated Factor 6, NFATC Transcription Factors, RANK Ligand
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