Autoamplification of NFATc1 expression determines its essential role in bone homeostasis
Open accessAbstract
NFATc1 and NFATc2 are functionally redundant in the immune system, but it was suggested that NFATc1 is required exclusively for differentiation of osteoclasts in the skeletal system. Here we provide genetic evidence that NFATc1 is essential for osteoclast differentiation in vivo by adoptive transfer of NFATc1−/− hematopoietic stem cells to osteoclast-deficient Fos−/− mice, and by Fos−/− blastocyst complementation, thus avoiding the embryonic lethality of NFATc1−/− mice. However, in vitro osteoclastogenesis in NFATc1-deficient cells was rescued by ectopic expression of NFATc2. The discrepancy between the in vivo essential role of NFATc1 and the in vitro effect of NFATc2 was attributed to selective autoregulation of the NFATc1 gene by NFAT through its promoter region. This suggested that an epigenetic mechanism contributes to the essential function of NFATc1 in cell lineage commitment. Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis.
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Canonical NF-κB signaling activation is initiated within one hour of RANKL binding and leads to induction of NFATc1 expression.
“Canonical NF-κB signaling activation is very fast, initiated within one hour of RANKL binding, and leads to the induction of NFATc1 expression.167”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [167]
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- Authors
- Asagiri, M., Sato, K., Usami, T., Ochi, S., Nishina, H., Yoshida, H., Morita, I., Wagner, E. F., Mak, T. W., Serfling, E., & Takayanagi, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Saga University (JP)
- Research Institute of Molecular Pathology (AT)
- University of Toronto (CA)
- University of Würzburg (DE)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2005-11-07
- Volume
- 202
- Issue
- 9
- Pages
- 1261-1269
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2213228
- OpenAlex
- W2122518329
- Cited by
- 849
- References
- 35
- Citations by year
- 2026: 20 · 2025: 34 · 2024: 32 · 2023: 40 · 2022: 40 · 2021: 52 · 2020: 59 · 2019: 60 · 2018: 62 · 2017: 52 · 2016: 34 · 2015: 46 · 2014: 43 · 2013: 36 · 2012: 42
- FWCI
- 10.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- 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, NFATc2, osteoclastogenesis, bone homeostasis, FOS, hematopoietic stem cells, blastocyst complementation, lineage commitment, bone disease therapy
- MeSH terms
- Animals, Blastocyst, Bone and Bones, Cell Differentiation, Cells, Cultured, Homeostasis, Liver, Osteoclasts, Promoter Regions, Genetic, Fetal Tissue Transplantation, Proto-Oncogene Proteins c-fos, Mice, Knockout, Epigenesis, Genetic, NFATC Transcription Factors, Mice
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