TGFβ‐induced factor homeobox 2 blocks osteoblastic differentiation through targeting pSmad3/HDAC4/H4ac/Runx2 axis
Abstract
TGFβ‐induced factor homeobox 2 ( Tgif2 ) has been reported as a functional role in cell homeostasis and a key activator of osteoclastogenesis and bone loss, as well. In the present study, we aimed to investigate the potential role of Tgif2 on osteogenic differentiation. Tgif2 expression was assessed during the osteogenic differentiation process of bone marrow‐derived mesenchymal stem cells (BMSCs) and primary calvarial osteoblasts (OBs). The expression of Tgif2 in BMSCs and OBs increased by using lentivirus‐mediated gene overexpression (OE). The effect of Tgif2 on osteogenic differentiation was compared between Tgif2 negative control ( Tgif2 ‐NC) and Tgif2 ‐OE group in BMSCs/OBs via performing alkaline phosphatase (ALP) assay, mineralization assay, and gene expression analysis of some osteogenic markers. To investigate the molecular mechanism, the direct interaction of histone deacetylase 4 (HDAC4) and pSmad3, acetylated histone H4 (H4ac), and Runx2 ‐binding site of the Ocn promoter was confirmed by performing co‐immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) assay, respectively. The results showed that Tgif2 abundantly expressed in BMSCs and primary calvarial OBs, but decreased after osteogenic induction. In vitro, osteogenic differentiation was significantly inhibited with Tgif2 overexpression in both BMSCs and OBs, as well as the expression levels of osteogenic markers ( Runx2, Sp7, Alp, and Ocn ). Moreover, we found that Tgif2 overexpression significantly promoted the interaction of pSmad3 with HDAC4 in differentiated OBs, and sequentially decreased the abundance of H4ac at the Runx2 ‐binding site of the Ocn promoter. These findings indicated that Tgif2 might block osteoblastic differentiation in vitro through targeting pSmad3/HDAC4/H4ac/Runx2 axis.
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Multiple homeobox genes have been implicated in bone mass and osteogenesis regulation.
“Multiple homeobox genes have been implicated in the regulation of bone mass and osteogenesis16–19.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [16]
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- Authors
- Yu, X., Shen, G., Ren, H., Zhang, Z., Shang, Q., Zhao, W., Huang, J., Yang, Z., Liang, D., & Jiang, X.
- Affiliations
- Guangzhou University of Chinese Medicine (CN)
- First Affiliated Hospital of Guangzhou University of Chinese Medicine (CN)
- Corresponding author
- Jiang, Xiaobing
- ORCID
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2019-05-07
- Volume
- 234
- Issue
- 11
- Pages
- 21284-21293
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- OpenAlex
- W2943921966
- Cited by
- 15
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 3 · 2019: 1
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Guangdong Province (1614050002812, 2016A030313645, 2014A030310082)
- Guangdong Provincial Department of Science and Technology (2016A020226006, 2014A020221021)
- China Postdoctoral Science Foundation (2017M610271)
- National Natural Science Foundation of China (81774338, 81674000, 81503591)
- 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
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- TGIF2, osteogenic differentiation, Smad3, HDAC4, histone H4 acetylation, Runx2, bone marrow-derived mesenchymal stem cells, calvarial osteoblasts, transcriptional repression
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Histone Deacetylases, Osteoblasts, Osteogenesis, Repressor Proteins, Signal Transduction, Homeodomain Proteins, Core Binding Factor Alpha 1 Subunit, Mice, Smad3 Protein
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