title: An HDAC Inhibitor, Entinostat/MS-275, Partially Prevents Delayed Cranial Suture Closure in Heterozygous Runx2 Null Mice.
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.
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Han-Sol
authors.initials: HS
authors.lastname: Bae
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Won-Joon
authors.initials: WJ
authors.lastname: Yoon
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.|Department of Periodontology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Young-Dan
authors.initials: YD
authors.lastname: Cho
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Rabia
authors.initials: R
authors.lastname: Islam
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Shin
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Bong-Soo
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Biomedical Knowledge Engineering Laboratory, Institute of Human-Environment Interface Biology, Seoul National University, Republic of Korea.
authors.forename: Jin-Muk
authors.initials: JM
authors.lastname: Lim
authors.affiliation: Interdisciplinary Program in Bioinformatics and CHO&KIM Genomics, Seoul National University, Seoul, Republic of Korea.
authors.forename: Min-Seok
authors.initials: MS
authors.lastname: Seo
authors.affiliation: Interdisciplinary Program in Bioinformatics and CHO&KIM Genomics, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo-Ae
authors.initials: SA
authors.lastname: Cho
authors.affiliation: Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Kang-Young
authors.initials: KY
authors.lastname: Choi
authors.affiliation: Department of Orthodontics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seung-Hak
authors.initials: SH
authors.lastname: Baek
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.|Biomedical Knowledge Engineering Laboratory, Institute of Human-Environment Interface Biology, Seoul National University, Republic of Korea.
authors.forename: Hong-Gee
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Woo
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hyun-Mo
authors.initials: HM
authors.lastname: Ryoo
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000009:adverse effects* / Q000494:pharmacology; D002973:Cleidocranial Dysplasia / Q000139:chemically induced / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D003393:Cranial Sutures / Q000196:embryology* / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006579:Heterozygote; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D055550:Protein Stability / Q000187:drug effects; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D001549:Benzamides; D050659:Core Binding Factor Alpha 1 Subunit; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C493716:Runx2 protein, mouse; C118739:entinostat
keywords: CLEIDOCRANIAL DYSPLASIA; HDI; MS-275; RUNX2; SKELETOGENESIS