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J Clin Invest. 2017 Sep 1;127(9):3339-3352. doi: 10.1172/JCI93521. Epub 2017 Jul 31.

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva.

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Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
iPS Cell-Based Drug Discovery, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
Department of Tissue Regeneration, Institute for Frontier Life and Medical Sciences, and.
Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan.
Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto, Japan.
Division of Molecular and Developmental Biology, National Institute of Genetics, Shizuoka, Japan.
Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Shizuoka, Japan.
Institute for Integrated Cell-Material Sciences (WPI-iCeMS).
Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, and.
Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.


Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs). Two different HO mouse models, an FOP model mouse expressing FOP-ACVR1 and an FOP-iPSC-based HO model mouse, revealed critical roles for mTOR signaling in vivo. Moreover, we identified ENPP2, an enzyme that generates lysophosphatidic acid, as a linker of FOP-ACVR1 and mTOR signaling in chondrogenesis. These results uncovered the crucial role of the Activin-A/FOP-ACVR1/ENPP2/mTOR axis in FOP pathogenesis.

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