An mTOR Signaling Modulator Suppressed Heterotopic Ossification of Fibrodysplasia Ossificans Progressiva

  • Stem Cell Reports. 2018 Nov 13;11(5):1106-1119. doi: 10.1016/j.stemcr.2018.10.007.
Kyosuke Hino  1 ,  Chengzhu Zhao  2 ,  Kazuhiko Horigome  1 ,  Megumi Nishio  3 ,  Yasue Okanishi  4 ,  Sanae Nagata  5 ,  Shingo Komura  6 ,  Yasuhiro Yamada  7 ,  Junya Toguchida  8 ,  Akira Ohta  4 ,  Makoto Ikeya  9
Affiliations
  • 1. iPS Cell-Based Drug Discovery, 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.
  • 2. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
  • 3. Department of Regeneration Sciences and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
  • 4. Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
  • 5. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
  • 6. Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
  • 7. Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
  • 8. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; Department of Regeneration Sciences and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto 606-8507, Japan; Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
  • 9. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: [email protected].
PMID: 30392977 DOI: 10.1016/j.stemcr.2018.10.007
Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disorder characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor gain-of-function mutations in ACVR1 (FOP-ACVR1), a type I receptor for bone morphogenetic proteins. Despite numerous studies, no drugs have been approved for FOP. Here, we developed a high-throughput screening (HTS) system focused on the constitutive activation of FOP-ACVR1 by utilizing a chondrogenic ATDC5 cell line that stably expresses FOP-ACVR1. After HTS of 5,000 small-molecule compounds, we identified two hit compounds that are effective at suppressing the enhanced chondrogenesis of FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and suppressed the heterotopic ossification (HO) of multiple model mice, including FOP-ACVR1 transgenic mice and HO model mice utilizing FOP-iPSCs. Furthermore, we revealed that one of the hit compounds is an mTOR signaling modulator that indirectly inhibits mTOR signaling. Our results demonstrate that these hit compounds could contribute to future drug repositioning and the mechanistic analysis of mTOR signaling.

Keywords
ACVR1; activin A; bone morphogenetic protein (BMP); endochondral ossification; fibrodysplasia ossificans progressiva (FOP); heterotopic ossification; high-throughput screening (HTS); induced pluripotent stem cell (iPSC); mammalian target of rapamycin (mTOR); transforming growth factor β (TGF-β).
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