Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15438-43. doi: 10.1073/pnas.1510540112. Epub 2015 Nov 30.

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-β 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-β 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.

Keywords: BMP; TGF; fibrodysplasia ossificans progressiva; heterotopic ossification; iPSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / metabolism*
  • Activins / pharmacology
  • Bone Morphogenetic Proteins / metabolism
  • Calcification, Physiologic / drug effects
  • Chondrogenesis / drug effects
  • Humans
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Myositis Ossificans / metabolism*
  • Myositis Ossificans / pathology
  • Myositis Ossificans / physiopathology
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Transforming Growth Factor beta
  • activin A
  • Activins
  • ACVR1 protein, human
  • Activin Receptors, Type I

Associated data

  • GEO/GSE62783
  • GEO/GSE69459