title: Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by heterotopic endochondral ossification in soft tissue. A mutation in the bone morphogenetic protein (BMP) receptor ALK2, R206H, has been identified in patients with typical FOP. In the present study, we established murine embryonic stem (ES) cells that express wild-type human ALK2 or typical mutant human ALK2 [ALK2(R206H)] under the control of the Tet-Off system. Although wild-type ALK2 and mutant ALK2(R206H) were expressed in response to a withdrawal of doxycycline (Dox), BMP signaling was activated only in the mutant ALK2(R206H)-expressing cells without the addition of exogenous BMPs. The Dox-dependent induction of BMP signaling was blocked by a specific kinase inhibitor of the BMP receptor. The mutant ALK2(R206H)-carrying cells showed Dox-regulated chondrogenesis in vitro, which occurred in co-operation with transforming growth factor-β1 (TGF-β1). Overall, our ES cells are useful for studying the molecular mechanisms of heterotopic ossification in FOP in vitro and for developing novel inhibitors of chondrogenesis induced by mutant ALK2(R206H) associated with FOP.
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan; Division of Orthodontics, Department of Human Development and Fostering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado-shi, Saitama 350-0283, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohte
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shin
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yoneyama
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Osawa
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Arei
authors.initials: A
authors.lastname: Miyamoto
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Tsukamoto
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Takato
authors.initials: T
authors.lastname: Mizuta
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Kokabu
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan; Division of Orthodontics, Department of Human Development and Fostering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado-shi, Saitama 350-0283, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Machiya
authors.affiliation: Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuda
authors.affiliation: Division of Orthodontics, Department of Human Development and Fostering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado-shi, Saitama 350-0283, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Suda
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan. Electronic address: katagiri@saitama-med.ac.jp.
authors.forename: Takenobu
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis; D004195:Disease Models, Animal; D004318:Doxycycline / Q000737:chemistry; D053595:Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation; D009221:Myositis Ossificans / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D050505:Mutant Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; D004318:Doxycycline
keywords: BMP receptor; Chondrocytes; Embryonic stem cells; Fibrodysplasia ossificans progressiva