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. Epub 2017 Jul 31.

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.

MeSH terms

  • Activins / metabolism*
  • Animals
  • Cell Differentiation
  • Chondrocytes / cytology
  • Chondrogenesis*
  • Embryonic Stem Cells / cytology
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Inhibitory Concentration 50
  • Lysophospholipids / metabolism
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myositis Ossificans / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Phosphoric Diester Hydrolases / metabolism
  • Point Mutation
  • Recombinant Proteins / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Lysophospholipids
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • activin A
  • Activins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • lysophosphatidic acid

Grant support

Partially