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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
Author(s) -
Chakkalakal Salin A,
Uchibe Kenta,
Convente Michael R,
Zhang Deyu,
Economides Aris N,
Kaplan Frederick S,
Pacifici Maurizio,
Iwamoto Masahiro,
Shore Eileen M
Publication year - 2016
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2820
Subject(s) - fibrodysplasia ossificans progressiva , heterotopic ossification , myositis ossificans , ossification , mutation , bone morphogenetic protein , medicine , endocrinology , cancer research , genetics , biology , anatomy , pathology , gene
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.