title: Neofunction of ACVR1 in fibrodysplasia ossificans progressiva.
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.affiliation: 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;
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Hino
authors.affiliation: 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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ikeya
authors.affiliation: 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;
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Horigome
authors.affiliation: 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;
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Omics Group, Genomic Science Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, 554-0022, Japan;
authors.forename: Hayao
authors.initials: H
authors.lastname: Ebise
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan;
authors.forename: Megumi
authors.initials: M
authors.lastname: Nishio
authors.affiliation: 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.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sekiguchi
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan;
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Shibata
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan;
authors.forename: Sanae
authors.initials: S
authors.lastname: Nagata
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: 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.
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism*; D028341:Activins / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D009221:Myositis Ossificans / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I
keywords: BMP; TGF; fibrodysplasia ossificans progressiva; heterotopic ossification; iPSC