2. Academic Validation
  3. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

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

  • J Clin Invest. 2017 Sep 1;127(9):3339-3352. doi: 10.1172/JCI93521.
Kyosuke Hino 1 2,  Kazuhiko Horigome 1 2,  Megumi Nishio 3,  Shingo Komura 4 5,  Sanae Nagata 1,  Chengzhu Zhao 4,  Yonghui Jin 3 6,  Koichi Kawakami 7 8,  Yasuhiro Yamada 4 9,  Akira Ohta 10,  Junya Toguchida 1 3 6 11,  Makoto Ikeya 4
Affiliations

Affiliations

  • 1 Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
  • 2 iPS Cell-Based Drug Discovery, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
  • 3 Department of Tissue Regeneration, Institute for Frontier Life and Medical Sciences, and.
  • 4 Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
  • 5 Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan.
  • 6 Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto, Japan.
  • 7 Division of Molecular and Developmental Biology, National Institute of Genetics, Shizuoka, Japan.
  • 8 Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Shizuoka, Japan.
  • 9 Institute for Integrated Cell-Material Sciences (WPI-iCeMS).
  • 10 Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, and.
  • 11 Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
PMID: 28758906 DOI: 10.1172/JCI93521
Abstract

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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