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Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation.
- Source :
-
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2016 Sep; Vol. 31 (9), pp. 1666-75. Date of Electronic Publication: 2016 Mar 12. - Publication Year :
- 2016
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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.<br /> (© 2016 American Society for Bone and Mineral Research.)
- Subjects :
- Animals
Bone and Bones abnormalities
Bone and Bones pathology
Cell Proliferation drug effects
Chondrocytes drug effects
Chondrocytes pathology
Disease Models, Animal
Disease Progression
Growth Plate drug effects
Growth Plate pathology
Homeostasis
Humans
Mice, Transgenic
Movement
Ossification, Heterotopic pathology
Osteogenesis
Pyrazoles pharmacology
Stilbenes pharmacology
Activin Receptors, Type I genetics
Extremities growth & development
Extremities physiopathology
Mutation genetics
Myositis Ossificans genetics
Ossification, Heterotopic drug therapy
Ossification, Heterotopic physiopathology
Pyrazoles therapeutic use
Stilbenes therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1523-4681
- Volume :
- 31
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
- Publication Type :
- Academic Journal
- Accession number :
- 26896819
- Full Text :
- https://doi.org/10.1002/jbmr.2820