We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation.
The ACVR1 R206H mutation found in fibrodysplasia ossificans progressiva increases human induced pluripotent stem cell-derived endothelial cell formation and collagen production through BMP-mediated SMAD1/5/8 signaling.
FOP-iMSCs possessing enhanced chondrogenic ability were transcriptionally distinguishable from resFOP-iMSCs and activated the SMAD1/5/8 and SMAD2/3 pathways at steady state.
Expression of the mutant ALK2-R206H receptor (FOP-ALK2) results in increased phosphorylation of the downstream Smad1 effector proteins and elevated basal BMP-dependent transcriptional reporter activity, indicating that FOP-ALK2 is constitutively active.
Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva.