Induction and Activation of the Transcription Factor NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts
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Signaling by RANKL is essential for terminal differentiation of monocytes/macrophages into osteoclasts. The TRAF6 and c-Fos signaling pathways both play important roles downstream of RANKL. We show here that RANKL selectively induces NFATc1 expression via these two pathways. RANKL also evokes Ca(2+) oscillations that lead to calcineurin-mediated activation of NFATc1, and therefore triggers a sustained NFATc1-dependent transcriptional program during osteoclast differentiation. We also show that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL.
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NFATc1 plays a master role in osteoclastogenesis by regulating expression of osteoclast-specific genes such as cathepsin K, DC-STAMP, TRAP, OSCAR and other genes involved in osteoclast resorptive functions.
“NFATc1 is a transcription factor that plays a master role in osteoclastogenesis168 by regulating the expression of osteoclast-specific genes such as cathepsin K, DC-STAMP, and tartrate-resistant acid phosphatase (TRAP) or that of osteoclast-associated receptor (OSCAR) and other genes involved in OC resorptive functions.169”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [169]
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- Authors
- Takayanagi, H., Kim, S., Koga, T., Nishina, H., Isshiki, M., Yoshida, H., Saiura, A., Isobe, M., Yokochi, T., Inoue, J.-I., Wagner, E. F., Mak, T. W., Kodama, T., & Taniguchi, T.
- Affiliations
- Japan Science and Technology Agency (JP)
- The University of Tokyo (JP)
- Kyushu University (JP)
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Research Institute of Molecular Pathology (AT)
- University of Toronto (CA)
- Corresponding author
- Taniguchi, Tadatsugu
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 3
- Issue
- 6
- Pages
- 889-901
- ISSN
- 1534-5807 (ISSN-L)
- OpenAlex
- W2017372504
- Cited by
- 2,701
- References
- 63
- Citations by year
- 2026: 85 · 2025: 83 · 2024: 91 · 2023: 106 · 2022: 124 · 2021: 145 · 2020: 167 · 2019: 153 · 2018: 155 · 2017: 121 · 2016: 112 · 2015: 153 · 2014: 154 · 2013: 120 · 2012: 128
- FWCI
- 34.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Precursory Research for Embryonic Science and Technology
- Japan Science and Technology Corporation
- Japan Orthopaedics and Traumatology Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Ministry of Health, Labour and Welfare
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- NFATc1, RANKL signaling, osteoclastogenesis, TRAF6, c-fos, calcineurin, calcium oscillations, transcription factor activation, transcriptional programs
- MeSH terms
- Animals, Carrier Proteins, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Gene Expression Regulation, Genetic Testing, Hematopoietic Stem Cells, Membrane Glycoproteins, Mice, Inbred C57BL, Nuclear Proteins, Osteoclasts, Promoter Regions, Genetic, Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, Signal Transduction, Proto-Oncogene Proteins c-fos, Cell Culture Techniques, Calcineurin, Calcium Signaling, Oligonucleotide Array Sequence Analysis, Active Transport, Cell Nucleus, TNF Receptor-Associated Factor 6, NFATC Transcription Factors, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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