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 language | English |
|---|---|
| Pages (from-to) | 1666-1675 |
| Number of pages | 10 |
| Journal | Journal of Bone and Mineral Research |
| Volume | 31 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 1 2016 |
| Externally published | Yes |
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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
Cite this
Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation. / Chakkalakal, Salin A.; Uchibe, Kenta; Convente, Michael R.; Zhang, Deyu; Economides, Aris N.; Kaplan, Frederick S.; Pacifici, Maurizio; Iwamoto, Masahiro; Shore, Eileen M.
In: Journal of Bone and Mineral Research, Vol. 31, No. 9, 01.09.2016, p. 1666-1675.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation
AU - Chakkalakal, Salin A.
AU - Uchibe, Kenta
AU - Convente, Michael R.
AU - Zhang, Deyu
AU - Economides, Aris N.
AU - Kaplan, Frederick S.
AU - Pacifici, Maurizio
AU - Iwamoto, Masahiro
AU - Shore, Eileen M.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - ACVR1
KW - FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP)
KW - HETEROTOPIC OSSIFICATION
KW - PALOVAROTENE
KW - RETINOIC ACID RECEPTOR (RAR)
UR - http://www.scopus.com/inward/record.url?scp=84985041077&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84985041077&partnerID=8YFLogxK
U2 - 10.1002/jbmr.2820
DO - 10.1002/jbmr.2820
M3 - Article
VL - 31
SP - 1666
EP - 1675
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
SN - 0884-0431
IS - 9
ER -