BMP2-activated Erk/MAP kinase stabilizes Runx2 by increasing p300 levels and histone acetyltransferase activity
Open accessAbstract
Runx2 is a critical transcription factor for osteoblast differentiation. Regulation of Runx2 expression levels and transcriptional activity is important for bone morphogenetic protein (BMP)-induced osteoblast differentiation. Previous studies have shown that extracellular signal-regulated kinase (Erk) activation enhances the transcriptional activity of Runx2 and that BMP-induced Runx2 acetylation increases Runx2 stability and transcriptional activity. Because BMP signaling induces Erk activation in osteoblasts, we sought to investigate whether BMP-induced Erk signaling regulates Runx2 acetylation and stability. Erk activation by overexpression of constitutively active MEK1 increased Runx2 transcriptional activity, whereas U0126, an inhibitor of MEK1/2, suppressed basal Runx2 transcriptional activity and BMP-induced Runx2 acetylation and stabilization. Overexpression of constitutively active MEK1 stabilized Runx2 protein via up-regulation of acetylation and down-regulation of ubiquitination. Erk activation increased p300 protein levels and histone acetyltransferase activity. Knockdown of p300 using siRNA diminished Erk-induced Runx2 stabilization. Overexpression of Smad5 increased Runx2 acetylation and stabilization. Erk activation further increased Smad-induced Runx2 acetylation and stabilization, whereas U0126 suppressed these functions. On the other hand, knockdown of Smad1 and Smad5 by siRNA suppressed both basal and Erk-induced Runx2 protein levels. Erk activation enhanced the association of Runx2 with p300 and Smad1. Taken together these results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300. In addition to the canonical Smad pathway, a BMP-induced non-Smad Erk signaling pathway cooperatively regulates osteoblast differentiation partly via increasing the stability and transcriptional activity of Runx2.
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This osteogenic effect happened via the BMP-2/Smad/Runx2/Osterix pathway.
“However, this happened via the BMP-2/Smad/Runx2/Osterix pathway, which revealed a new connection as BMP-2 had been related earlier to the Erk/MAP kinase pathway [43].”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [43]
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“However, this happened via the BMP-2/Smad/Runx2/Osterix pathway, which revealed a new connection as BMP-2 had been related earlier to the Erk/MAP kinase pathway [43].”
- Authors
- Jun, J. H., Yoon, W.-J., Seo, S.-B., Woo, K.-M., Kim, G.-S., Ryoo, H.-M., & Baek, J.-H.
- Affiliations
- Seoul National University (KR)
- Chung-Ang University (KR)
- Corresponding author
- Ryoo, Hyun-Mo
- Baek, Jeong-Hwa
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 285
- Issue
- 47
- Pages
- 36410-36419
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2978570
- OpenAlex
- W2042125973
- Cited by
- 167
- References
- 56
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 13 · 2019: 12 · 2018: 9 · 2017: 15 · 2016: 6 · 2015: 5 · 2014: 14 · 2013: 14 · 2012: 18
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Research Foundation
- National Research Foundation of Korea
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Runx2, BMP signaling, ERK MAP kinase, P300, histone acetyltransferase, protein acetylation, protein stability, osteogenic differentiation, Smad1, Smad5, MEK1, ubiquitination, transcriptional regulation
- MeSH terms
- Acetylation, Animals, Cell Differentiation, Cells, Cultured, Humans, Luciferases, RNA, Messenger, Blotting, Western, Signal Transduction, Transcriptional Activation, Up-Regulation, Mutagenesis, Site-Directed, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinases, Myoblasts, RNA, Small Interfering, Immunoprecipitation, Extracellular Signal-Regulated MAP Kinases, Core Binding Factor Alpha 1 Subunit, E1A-Associated p300 Protein, Mice, Histone Acetyltransferases, Smad Proteins, Ubiquitination, Bone Morphogenetic Protein 2
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