Essential Role of p38 Mitogen-activated Protein Kinase in Cathepsin K Gene Expression during Osteoclastogenesis through Association of NFATc1 and PU.1
Open accessAbstract
The receptor activator of NF-kappaB ligand (RANKL) induces various osteoclast-specific marker genes during osteoclast differentiation mediated by mitogen-activated protein (MAP) kinase cascades. However, the results of transcriptional programming of an osteoclast-specific cathepsin K gene are inconclusive. Here we report the regulatory mechanisms of RANKL-induced cathepsin K gene expression during osteoclastogenesis in a p38 MAP kinase-dependent manner. The reporter gene analysis with sequential 5'-deletion constructs of the cathepsin K gene promoter indicates that limited sets of the transcription factors such as NFATc1, PU.1, and microphthalmia transcription factor indeed enhance synergistically the gene expression when overexpressed in RAW264 cells. In addition, the activation of p38 MAP kinase is required for the maximum enhancement of the gene expression. RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. These results suggest that the RANKL-induced cathepsin K gene expression is cooperatively regulated by the combination of the transcription factors and p38 MAP kinase in a gradual manner.
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By interacting with transcription factors PU.1, cFos, and MITF, NFATc1 regulates osteoclast-specific genes including TRAP and cathepsin K, which are crucial for osteoclast activity.
“By interacting with the transcription factors PU.1, cFos, and MITF, NFATc1 regulates osteoclast-specific genes including TRAP and cathepsin K, which are crucial for osteoclast activity [90].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [90]
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- Authors
- Matsumoto, M., Kogawa, M., Wada, S., Takayanagi, H., Tsujimoto, M., Katayama, S., Hisatake, K., & Nogi, Y.
- Affiliations
- Saitama Medical University (JP)
- Tokyo Medical and Dental University (JP)
- RIKEN (JP)
- Corresponding author
- Matsumoto, Masahito
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 279
- Issue
- 44
- Pages
- 45969-45979
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2030075526
- Cited by
- 436
- References
- 63
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 15 · 2023: 14 · 2022: 30 · 2021: 20 · 2020: 33 · 2019: 21 · 2018: 27 · 2017: 18 · 2016: 18 · 2015: 33 · 2014: 22 · 2013: 17 · 2012: 31
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Kowa Company
- Kowa Life Science Foundation
- 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 › Protease and Inhibitor Mechanisms
- Keywords
- p38 MAPK, cathepsin K, osteoclastogenesis, RANKL, NFATc1, PU.1, transcriptional regulation, promoter, microphthalmia-associated transcription factor, transcription factor complex
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Carrier Proteins, Cathepsins, Cell Differentiation, DNA-Binding Proteins, Humans, Membrane Glycoproteins, Mice, Inbred C57BL, Nuclear Proteins, Osteoclasts, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins, Recombinant Proteins, Transcription Factors, Trans-Activators, Gene Expression Regulation, Enzymologic, p38 Mitogen-Activated Protein Kinases, NFATC Transcription Factors, Mice, Microphthalmia-Associated Transcription Factor, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Cathepsin K
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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