Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation

Salin A. Chakkalakal, Kenta Uchibe, Michael R. Convente, Deyu Zhang, Aris N. Economides, Frederick S. Kaplan, Maurizio Pacifici, Masahiro Iwamoto, Eileen M. Shore

Research output: Contribution to journalArticle

56 Citations (Scopus)

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, ACVR1R206H, 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 ACVR1R206H 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.

Original languageEnglish
Pages (from-to)1666-1675
Number of pages10
JournalJournal of Bone and Mineral Research
Volume31
Issue number9
DOIs
Publication statusPublished - Sep 1 2016
Externally publishedYes

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Keywords

  • ACVR1
  • FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP)
  • HETEROTOPIC OSSIFICATION
  • PALOVAROTENE
  • RETINOIC ACID RECEPTOR (RAR)

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)
  • Orthopedics and Sports Medicine

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