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Regulation of NFATc1 in Osteoclast Differentiation
Open accessAbstract
Osteoclasts are unique cells that degrade the bone matrix. These large multinucleated cells differentiate from the monocyte/macrophage lineage upon stimulation by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL). Activation of transcription factors such as microphthalmia transcription factor (MITF), c-Fos, NF-κB, and nuclear factor-activated T cells c1 (NFATc1) is required for sufficient osteoclast differentiation. In particular, NFATc1 plays the role of a master transcription regulator of osteoclast differentiation. To date, several mechanisms, including transcription, methylation, ubiquitination, acetylation, and non-coding RNAs, have been shown to regulate expression and activation of NFATc1. In this review, we have summarized the various mechanisms that control NFATc1 regulation during osteoclast differentiation.
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“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 [20]
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“In RANKL-activated HSCs, polyubiquitination of NIK is inhibited [18], and TRAF6 activates a cascade of kinases, including extracellular regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-jun N-terminal kinase (JNK), phosphatidylinositol-3 kinase (PI3K), and Akt and IkB kinases [20,21].”
From Osteoclasts and Microgravity (2020) · cites this paper as [20]
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“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 [20]
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“Among genes harboring an excess of HF SNCs associated with specific facial features, we find RUNX2, EDAR, and GLI3133, NFATC1134, SPOP135, DDR2136 and NELL1137, possibly carrying changes in regulatory regions”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [134]
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“NFATc1, whose overexpression can drive OC formation independently of RANKL, is a critical transcription factor which is essential for osteoclastogenesis [28].”
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“RANKLRANK interaction activates the master transcription factor for osteoclastogenesis; nuclear factor of activated T cells, cytoplasmic 1 (NFATc1); tartrate-resistant acid phosphatase; calcitonin receptor; and cathepsin K [27].”
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“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…”
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“Activated AKT inhibits GSK-3β, which subsequently downregulates NFATc1 expression [76,77], and this reduces osteoclast differentiation [78].”
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“In addition, the RANKL-RANK interaction induces the expression of transcription factors, including nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a key transcription factor for osteoclastogenesis both in vitro and in vivo (Takayanagi 2007; Kim and Kim 2014).”
BackgroundJMJD3: a critical epigenetic regulator in stem cell fate
Ding, Y., Yao, Y., Gong, X., Zhuo, Q., Chen, J., Tian, M., & Farzaneh, M. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00753-8 · Cited by 46
The Multiple Roles of Microrna-223 in Regulating Bone Metabolism
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“RelB/p52 heterodimers can translocate to the nucleus to induce nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) [61], which is necessary for osteoclast”
BackgroundHe, L., Duan, H., Li, X., Wang, S., Zhang, Y., Lei, L.-S., Xu, J., Liu, S., & Li, X. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.03.014 · Cited by 44
Transcriptional Regulation of Osteoclastogenesis: The Emerging Role of KLF2
Rolph, D. N., & Das, H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00937 · Cited by 43
“Intermediate signals downstream of TRAF6 are mediated via NF-κB and c-Fos (Figure 2) (45).”
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Mustafa, N. H., Sekar, M., Fuloria, S., Begum, M. Y., Gan, S. H., Rani, N. N. I. M., Ravi, S., Chidambaram, K., Subramaniyan, V., Sathasivam, K. V., et al. (2022) · Molecules · doi:10.3390/molecules27062032 · Cited by 46
Microbiota metabolites in bone: Shaping health and Confronting disease
Han, D., Wang, W., Gong, J., Ma, Y., & Li, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28435 · Cited by 46
“This transcription factor is essential for osteoclast cell growth and is thought to be found in the nucleus of osteoclast progenitors [207,208].”
BackgroundCircadian Regulation of Bone Remodeling
Kikyo, N. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094717 · Cited by 43
“NFATc1 activates many osteoclast-specific genes, including cathepsin K ( Ctsk ), tartrate-resistant acid phosphatase 5 ( Trap or Acp5 , a marker protein widely used to detect osteoclasts via enzyme histochemistry), and calcitonin receptor ( Calcr ) [41].”
BackgroundWang, Q., Yao, L., Ke Cheng, X. U., Jin, H., Chen, K., Wang, Z., Liu, Q., Cao, Z., Kenny, J., Liu, Y., et al. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13942 · Cited by 43
“Therefore, we propose that MA can regulate the activation of AP‐1 F IGURE 10 A schematic diagram helps in understanding the role of Madecassoside in suppressing RANKL‐ induced osteoclastogenesis by interfering with MAPK signaling and inhibiting the subsequent induction of NFATc1.”
BackgroundInfluentialRaimondi, L., Luca, A. D., Fontana, S., Amodio, N., Costa, V., Carina, V., Bellavia, D., Raimondo, S., Siragusa, S. M., Monteleone, F., et al. (2020) · Cancers · doi:10.3390/cancers12082167 · Cited by 43
The hidden secrets of soluble RANKL in bone biology
Elango, J., Bao, B., & Wu, W. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155559 · Cited by 47
AMPK negatively regulates RANKL-induced osteoclast differentiation by controlling oxidative stress
Tanaka, M., Inoue, H., Takahashi, N., & Uehara, M. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.05.033 · Cited by 41
Periodontal materials and cell biology for guided tissue and bone regeneration
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Pathogenesis of Periodontal Disease
Muñoz‐Carrillo, J. L., Hernández-Reyes, V. E., García-Huerta, O. E., Chávez-Ruvalcaba, F., Chávez-Ruvalcaba, M. I., Chávez-Ruvalcaba, K. M., & Díaz-Alfaro, L. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.86548 · Cited by 41
“RANKL is a cytokine member of the TNF family that can be bound or secreted to the membrane and stimulates the differentiation of osteoclasts, cell fusion, and activation that leads to bone resorption [40, 41].”
BackgroundAllison, H., & McNamara, L. M. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00168.2019 · Cited by 41
Arnst, J. L., Jing, Z., Cohen, C. I., Ha, S., Viggeswarapu, M., & Beck, G. R. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122238 · Cited by 40
Directed Differentiation of Human Induced Pluripotent Stem Cells to Heart Valve Cells
Cai, Z., Zhu, M., Xu, L., Wang, Y., Xu, Y., Yim, W. Y., Cao, H., Guo, R., Qiu, X., He, X., et al. (2024) · Circulation · doi:10.1161/circulationaha.123.065143 · Cited by 40
“33,34 Therefore, we selected 3 different Ca 2+ channel activators (forskolin, Bay K 8644, and FPL 64176) or RANKL combined with VEGF-165 to promote the differentiation of heart valve cells from hiCLPM.”
MethodKwak, S. C., Baek, J. M., Lee, C. H., Yoon, K., Lee, M. S., & Kim, J. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.28609 · Cited by 40
“These two distinct signaling pathways activate nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is a key transcription regulator of osteoclast differentiation, inducing the release of a number of osteoclast-specific genes, such as tartrate-resistant acid phosphatase (TRAP), osteoclast-associated recep…”
BackgroundSelf-citationLiu, W.-C., Shyu, J., Lim, P., Fang, T., Lu, C., Zheng, C., Hou, Y., Wu, C., Lin, Y., & Lu, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103486 · Cited by 42
“The nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), one of AhR target proteins, plays an important role in osteoclast precursor differentiation [16] and is a major transcription factor for osteoclastogenesis [17].”
BackgroundHairi, H. A., Jayusman, P. A., & Shuid, A. N. (2023) · Biomedicines · doi:10.3390/biomedicines11051453 · Cited by 41
Endoplasmic Reticulum–Bound Transcription Factor CREBH Stimulates RANKL-Induced Osteoclastogenesis
Kim, J. H., Kim, K., Kim, I., Seong, S., Kim, K. K., Kim, N., & Kim, N. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701036 · Cited by 39
Self-citationWehrhan, F., Groß, C., Creutzburg, K., Amann, K., Ries, J., Kesting, M. R., Geppert, C., & Weber, M. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1819-1 · Cited by 42
The KDM4B–CCAR1–MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis
Yi, S.-J., Jang, Y.-J., Kim, H., Lee, K., Lee, H.-R., Kim, Y., Kim, J., Hwang, S. Y., Song, J. S., Okada, H., et al. (2021) · Bone Research · doi:10.1038/s41413-021-00145-1 · Cited by 39
“NT (1-660) CT (661-1 146) SAP Coiled-coil (792-819)”
Self-citationJeong, B., Kim, J. H., Kim, K., Kim, I., Seong, S., & Kim, N. (2016) · Bone · doi:10.1016/j.bone.2016.11.005 · Cited by 35
Self-citationGranchi, D., Torreggiani, E., Massa, A., Caudarella, R., Pompo, G. D., & Baldini, N. (2017) · PLoS ONE · doi:10.1371/journal.pone.0181230 · Cited by 37
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“NFATc1 is a critical transcription factor in promoting RANKL-induced osteoclastogenesis by activating the transcription of genes involved in osteoclast differentiation and activity [21].”
BackgroundNarahara, S., Sakai, E., Kadowaki, T., Yamaguchi, Y., Narahara, H., Okamoto, K., Asahina, I., & Tsukuba, T. (2019) · Scientific Reports · doi:10.1038/s41598-019-40240-2 · Cited by 38
Choo, Y.-Y., Trần, P. T., Min, B.-S., Kim, O., Nguyen, H. D., Kwon, S., & Lee, J. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.09.018 · Cited by 36
Development of PEI- RANK siRNA Complex Loaded PLGA Nanocapsules for the Treatment of Osteoporosis
Bilecen, D., Uludağ, H., & Hasırcı, V. (2018) · Tissue Engineering Part A · doi:10.1089/ten.tea.2017.0476 · Cited by 36
“9 It regulates the expression of osteoclast specific genes such as tartrate resistant acid phosphatase ( TRAP ), Cathepsin K, and calcitonin receptor, 9,10 and therefore, osteoclastic differentiation is initiated (Fig.”
Toxic Effects of Indoxyl Sulfate on Osteoclastogenesis and Osteoblastogenesis
Shyu, J., Liu, W.-C., Zheng, C., Fang, T., Hou, Y., Chang, C., Liao, T.-Y., Chen, Y.-C., & Lu, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011265 · Cited by 36
“In the differentiation stage of osteoclast precursors, the nuclear factor of activated cytoplasmic T lymphocytes 1 (NFATc1) plays a dominant role [111].”
BackgroundHwang, Y., Jang, S., Lee, A., Cho, C., Song, Y., Hong, H., Ha, H., & Kim, T. S. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.06.059 · Cited by 35
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“NFATc1 can also activate the expression of genes that typify the osteoclast lineage including CTSK, MMP9, and TRAP, leading to the eventual formation of mature osteoclasts [5, 40].”
BackgroundSrivastava, S., & Rasool, M. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.123075 · Cited by 34
STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis
Lee, J., Seong, S., Kim, J. H., Kim, K., Kim, I., Jeong, B., Nam, K. I., Kim, K. K., Hennighausen, L. G., & Kim, N. (2016) · Scientific Reports · doi:10.1038/srep30977 · Cited by 34
Self-citationKim, J. H., Sim, J. H., Lee, S., Seol, M. A., Ye, S., Shin, H. M., Lee, E. B., Lee, Y. J., Choi, Y. J., Yoo, W., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01376 · Cited by 34
“Furthermore, we explored whether the expression of nuclear factor of activated T-cells 1 (NFATc1), a master regulator gene that is upregulated by RANKL, was affected by IL-7 during osteoclastogenesis because RANKL upregulates NFATc1 via the expression of the early osteoclastic gene, c-Fos, which, in turn, induces oste…”
BackgroundSelf-citationLee, W., Ko, K. R., Kim, H.-K., Lee, D. S., Nam, I.-J., Lim, S., & Kim, S. (2018) · Journal of Natural Products · doi:10.1021/acs.jnatprod.7b00927 · Cited by 33
Florczyk, U., Józefczuk, E., Stępniewski, J., Bukowska-Straková, K., Mendel, M., Viscardi, M., Nowak, W. N., Józkowicz, A., & Dulak, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-29122-1 · Cited by 34
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“Interestingly, loss of Acer1 did not reduce the expression of the Sox9, Nfatc1, and Lgr5 in HFSCs (Figure S6B), although these genes are known downstream targets of Lhx2 (Kim and Kim, 2014; Kim et al., 2014; Mardaryev et al., 2011), suggesting that loss of Acer1 reduces HFSC quiescence through an unknown target(s) of…”
InfluentialHwang, Y., Ha, H., 김라정, Cho, C., Song, Y., Hong, H., & Kim, T. S. (2018) · Nutrients · doi:10.3390/nu10070901 · Cited by 33
“RANKL binding to its receptor RANK initially activates both the MAPK and NF-κB pathways, which are essential signal pathways in the formation, activation, and survival of osteoclasts [33].”
BackgroundInfluentialCurrent perspectives of osteoclastogenesis through estrogen modulated immune cell cytokines
Uehara, I. A., Soldi, L. R., & Silva, M. J. B. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117921 · Cited by 34
Metadata
- Authors
- Kim, J. H., & Kim, N.
- Affiliations
- Chonnam National University (KR)
- Corresponding author
- Kim, Nacksung
- Venue
- Journal of Bone Metabolism
- Published
- 2014
- Volume
- 21
- Issue
- 4
- Pages
- 233
- ISSN
- 2287-6375 (ISSN-L)
- 2287-7029
- PMC
- PMC4255043
- OpenAlex
- W2132541910
- Cited by
- 570
- References
- 69
- Citations by year
- 2026: 54 · 2025: 43 · 2024: 54 · 2023: 64 · 2022: 58 · 2021: 57 · 2020: 68 · 2019: 51 · 2018: 46 · 2017: 31 · 2016: 26 · 2015: 17
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Bone Metabolism (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- NFATc1, osteoclastogenesis, transcriptional regulation, epigenetic regulation, DNA methylation, ubiquitination, acetylation, non-coding RNA, macrophage colony-stimulating factor, RANKL, MITF, c-fos, NF-κB, bone resorption
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