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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-? 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-? 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.

SUBMITTER: Hino K 

PROVIDER: S-EPMC4687587 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Neofunction of ACVR1 in fibrodysplasia ossificans progressiva.

Hino Kyosuke K   Ikeya Makoto M   Horigome Kazuhiko K   Matsumoto Yoshihisa Y   Ebise Hayao H   Nishio Megumi M   Sekiguchi Kazuya K   Shibata Mitsuaki M   Nagata Sanae S   Matsuda Shuichi S   Toguchida Junya J  

Proceedings of the National Academy of Sciences of the United States of America 20151130 50

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 (F  ...[more]

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