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Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):347-52. doi: 10.1016/j.bbrc.2014.11.012. Epub 2014 Nov 15.

Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2.

Author information

1
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.
2
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
3
Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
4
Division of Orthodontics, Department of Human Development and Fostering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado-shi, Saitama 350-0283, Japan.
5
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.

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.

KEYWORDS:

BMP receptor; Chondrocytes; Embryonic stem cells; Fibrodysplasia ossificans progressiva

PMID:
25446088
DOI:
10.1016/j.bbrc.2014.11.012
[Indexed for MEDLINE]

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