Fibrodysplasia ossificans progressiva (FOP), a rare and as yet untreatable 
genetic disorder of progressive extraskeletal ossification, is the most 
disabling form of heterotopic ossification (HO) in humans and causes skeletal 
deformities, movement impairment, and premature death. Most FOP patients carry 
an activating mutation in a bone morphogenetic protein (BMP) type I receptor 
gene, ACVR1(R206H) , that promotes ectopic chondrogenesis and osteogenesis and, 
in turn, HO. We showed previously that the retinoic acid receptor γ (RARγ) 
agonist palovarotene effectively inhibited HO in injury-induced and genetic 
mouse models of the disease. Here we report that the drug additionally prevents 
spontaneous HO, using a novel conditional-on knock-in mouse line carrying the 
human ACVR1(R206H) mutation for classic FOP. In addition, palovarotene restored 
long bone growth, maintained growth plate function, and protected growing mutant 
neonates when given to lactating mothers. Importantly, palovarotene maintained 
joint, limb, and body motion, providing clear evidence for its encompassing 
therapeutic potential as a treatment for FOP. © 2016 American Society for Bone 
and Mineral Research.