title: Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation.
abstract: 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.
authors.affiliation: Department of Orthopedic Surgery, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Salin A
authors.initials: SA
authors.lastname: Chakkalakal
authors.affiliation: The Children's Hospital of Philadelphia, Division of Orthopedic Surgery, Philadelphia, PA, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Uchibe
authors.affiliation: Department of Orthopedic Surgery, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Convente
authors.affiliation: Department of Orthopedic Surgery, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Deyu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Department of Orthopedic Surgery, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.|Department of Medicine, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.affiliation: The Children's Hospital of Philadelphia, Division of Orthopedic Surgery, Philadelphia, PA, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pacifici
authors.affiliation: The Children's Hospital of Philadelphia, Division of Orthopedic Surgery, Philadelphia, PA, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Department of Orthopedic Surgery, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.|Department of Genetics, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005121:Extremities / Q000254:growth & development* / Q000503:physiopathology*; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008822:Mice, Transgenic; D009068:Movement; D009154:Mutation / Q000235:genetics*; D009221:Myositis Ossificans / Q000235:genetics*; D009999:Ossification, Heterotopic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D010012:Osteogenesis; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D011720:Pyrazoles; D013267:Stilbenes; C546535:Palovarotene; D030201:Activin Receptors, Type I
keywords: ACVR1; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP); HETEROTOPIC OSSIFICATION; PALOVAROTENE; RETINOIC ACID RECEPTOR (RAR)