Ca 2+ ‐NFATc1 signaling is an essential axis of osteoclast differentiation
Abstract
Osteoclasts are unique, multinucleated giant cells that decalcify and degrade the bone matrix. They originate from hematopoietic cells and their differentiation is dependent on a tumor necrosis factor (TNF) family cytokine, receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL), as well as macrophage-colony stimulating factor (M-CSF). Recent studies have unveiled the precise molecular mechanism underlying osteoclastogenesis. In particular, the discovery of nuclear factor of activated T cells c1 (NFATc1), the master regulator of osteoclastogenesis, has proven to be a breakthrough in this field. NFATc1 is activated by Ca2+ signaling induced by the activation of the immunoglobulin-like receptor signaling associated with immunoreceptor tyrosine-based activation motif (ITAM)-harboring adapters. The long-lasting Ca2+ oscillation, which is evident during osteoclastogenesis, may ensure the robust induction of NFATc1 through an autoamplification mechanism. Thus, intracellular Ca2+ is a critical attribute of osteoclastogenic signaling. In addition, osteoclasts are exposed to a very high extracellular Ca2+ concentration ([Ca2+]o) in the bone microenvironment and respond to the change in [Ca2+]o by increasing the intracellular Ca2+, which regulates diverse cellular functions. Investigation of the molecular mechanisms underlying the regulation of intracellular Ca2+ dynamics may open up new directions for therapeutic strategies in bone disease.
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The calcineurin pathway is a key costimulatory pathway of NFATc1 and an important signaling component of a number of immune cell receptors.
“This activates cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and the calcineurin pathway [21,24,25,27], a key costimulatory pathway of NFATc1 [21,23] and an important signaling component of a number of immune cell receptors [28] (Figure 4 and Figure 5).”
From Osteoclasts and Microgravity (2020) · cites this paper as [24]
The RANKL-activated kinase cascade requires Lys63-linked TRAF-6 auto-ubiquitination and initiates transcription of AP-1, c-Fos, NF-κB, and NFATc1, the master regulator of osteoclast differentiation.
“This cascade requires Lys63-linked TRAF-6 auto-ubiquitination [22] and initiates the transcription of activator protein-1 (AP-1), c-Fos, NF-κB, and nuclear factor of activated T cells cytoplasmic calcineurin-dependent 1 (NFATc1), the master regulator of osteoclast differentiation [20,23,24].”
From Osteoclasts and Microgravity (2020) · cites this paper as [24]
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de la Rica, L., Rodríguez-Ubreva, J., García, M., Islam, A. B., Urquiza, J. M., Hernando, H., Christensen, J., Helin, K., Gómez-Vaquero, C., & Ballestar, E. (2013) · Genome Biology · doi:10.1186/gb-2013-14-9-r99 · Cited by 211 · see citing works
“The signaling pathways activated after M-CSF and RANKL induction have been extensively described, and act through TRAF-6 [8,9], immunoreceptor tyrosine-based activation motif (ITAM) [10] adaptors DAP12 [11] and FcRγ [12] associated with their respective receptors, TREM-2 [13] and OSCAR, as well as calcium oscillations…”
Hallmarks of peripheral nerve function in bone regeneration
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Smith, J. K. (2020) · Life · doi:10.3390/life10090207 · Cited by 52 · see citing works
“This activates cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and the calcineurin pathway [21,24,25,27], a key costimulatory pathway of NFATc1 [21,23] and an important signaling component of a number of immune cell receptors [28] (Figures 4 and 5).”
Background
- Authors
- Negishi‐Koga, T., & Takayanagi, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Takayanagi, Hiroshi
- ORCID
- Negishi‐Koga, Takako
- Venue
- Immunological Reviews
- Publisher
- Wiley
- Published
- 2009-09
- Volume
- 231
- Issue
- 1
- Pages
- 241-256
- ISSN
- 0105-2896 (ISSN-L)
- 1600-065X
- OpenAlex
- W2096542991
- Cited by
- 415
- References
- 10
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 19 · 2023: 28 · 2022: 23 · 2021: 25 · 2020: 39 · 2019: 25 · 2018: 30 · 2017: 17 · 2016: 31 · 2015: 19 · 2014: 25 · 2013: 23 · 2012: 28
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Immunological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation
- Japan Society for the Promotion of Science
- 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
- osteoclastogenesis, NFATc1, calcium signaling, intracellular calcium dynamics, RANKL, macrophage colony-stimulating factor, ITAM signaling, calcium oscillations, extracellular calcium, bone resorption, bone disease therapy
- MeSH terms
- Animals, Cell Differentiation, Humans, Osteoclasts, Macrophage Colony-Stimulating Factor, Calcium Signaling, NFATC Transcription Factors, RANK Ligand
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