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Neofunction of ACVR1 in fibrodysplasia ossificans progressiva.
Proc Natl Acad Sci U S A. 2015 Dec 15; 112(50):15438-43.PN

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and ligand-dependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP.

Authors+Show Affiliations

Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan; iPS Cell-Based Drug Discovery Group, Innovative Drug Discovery Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, 554-0022, Japan;Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan; mikeya@cira.kyoto-u.ac.jp togjun@frontier.kyoto-u.ac.jp.Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan; iPS Cell-Based Drug Discovery Group, Innovative Drug Discovery Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, 554-0022, Japan;Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan; Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan;Omics Group, Genomic Science Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, 554-0022, Japan;Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan;Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan; Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan; Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan;Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan;Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan; Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan; Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan mikeya@cira.kyoto-u.ac.jp togjun@frontier.kyoto-u.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26621707

Citation

Hino, Kyosuke, et al. "Neofunction of ACVR1 in Fibrodysplasia Ossificans Progressiva." Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 50, 2015, pp. 15438-43.
Hino K, Ikeya M, Horigome K, et al. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA. 2015;112(50):15438-43.
Hino, K., Ikeya, M., Horigome, K., Matsumoto, Y., Ebise, H., Nishio, M., Sekiguchi, K., Shibata, M., Nagata, S., Matsuda, S., & Toguchida, J. (2015). Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proceedings of the National Academy of Sciences of the United States of America, 112(50), 15438-43. https://doi.org/10.1073/pnas.1510540112
Hino K, et al. Neofunction of ACVR1 in Fibrodysplasia Ossificans Progressiva. Proc Natl Acad Sci USA. 2015 Dec 15;112(50):15438-43. PubMed PMID: 26621707.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. AU - Hino,Kyosuke, AU - Ikeya,Makoto, AU - Horigome,Kazuhiko, AU - Matsumoto,Yoshihisa, AU - Ebise,Hayao, AU - Nishio,Megumi, AU - Sekiguchi,Kazuya, AU - Shibata,Mitsuaki, AU - Nagata,Sanae, AU - Matsuda,Shuichi, AU - Toguchida,Junya, Y1 - 2015/11/30/ PY - 2015/12/2/entrez PY - 2015/12/2/pubmed PY - 2016/5/10/medline KW - BMP KW - TGF KW - fibrodysplasia ossificans progressiva KW - heterotopic ossification KW - iPSC SP - 15438 EP - 43 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 112 IS - 50 N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and ligand-dependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/26621707/Neofunction_of_ACVR1_in_fibrodysplasia_ossificans_progressiva_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=26621707 DB - PRIME DP - Unbound Medicine ER -