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Updated: Mar 9, 2026
Neural Tube Closure in Mouse Whole Embryo Culture
Published on: October 21, 2011
An HDAC Inhibitor, Entinostat/MS-275, Partially Prevents Delayed Cranial Suture Closure in Heterozygous Runx2 Null
Han-Sol Bae1, Won-Joon Yoon1, Young-Dan Cho1,2
1Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
Abstract:
Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder caused by mutations in RUNX2, coding a key transcription factor of early osteogenesis. CCD patients suffer from developmental defects in cranial bones. Despite numerous investigations and clinical approaches, no therapeutic strategy has been suggested to prevent CCD. Here, we show that fetal administration of Entinostat/MS-275, a class I histone deacetylase (HDAC)-specific inhibitor, partially prevents delayed closure of cranial sutures in Runx2+/- mice strain of C57BL/6J by two mechanisms: 1) posttranslational acetylation of Runx2 protein, which stabilized the protein and activated its transcriptional activity; and 2) epigenetic regulation of Runx2 and other bone marker genes. Moreover, we show that MS-275 stimulates osteoblast proliferation effectively both in vivo and in vitro, suggesting that delayed skeletal development in CCD is closely related to the decreased number of progenitor cells as well as the delayed osteogenic differentiation. These findings provide the potential benefits of the therapeutic strategy using MS-275 to prevent CCD. © 2017 American Society for Bone and Mineral Research.
Insights
Fetal administration of Entinostat (MS-275), an HDAC inhibitor, partially prevents cranial suture defects in a mouse model of cleidocranial dysplasia (CCD). This treatment stabilizes RUNX2 protein and enhances osteoblast proliferation, offering a potential therapeutic strategy for CCD.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Pharmacology
Background:
- Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder.
- Mutations in RUNX2, a key transcription factor for osteogenesis, cause CCD and lead to cranial bone developmental defects.
- Currently, no effective therapeutic strategy exists for CCD.
Purpose of the Study:
- To investigate the potential therapeutic effects of Entinostat (MS-275), a class I histone deacetylase (HDAC)-specific inhibitor, on cleidocranial dysplasia.
- To elucidate the mechanisms by which MS-275 may prevent skeletal developmental defects in CCD.
Main Methods:
- Fetal administration of MS-275 in Runx2+/- mice (C57BL/6J strain).
- Analysis of cranial suture closure, RUNX2 protein acetylation and stability, gene expression of bone markers, and osteoblast proliferation in vivo and in vitro.
Main Results:
- Fetal MS-275 administration partially prevented delayed cranial suture closure in Runx2+/- mice.
- MS-275 enhanced RUNX2 protein stability and transcriptional activity through posttranslational acetylation.
- MS-275 demonstrated epigenetic regulation of RUNX2 and other bone marker genes.
- MS-275 effectively stimulated osteoblast proliferation both in vivo and in vitro.
Conclusions:
- Delayed skeletal development in CCD may be linked to reduced progenitor cell numbers and impaired osteogenic differentiation.
- MS-275 shows potential as a therapeutic strategy to prevent cleidocranial dysplasia by stabilizing RUNX2 and promoting osteoblast activity.
