Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation.
Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation.
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DOI：
10.1002/jbmr.2820
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Shore EM
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文献类型：
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作者：
Chakkalakal SA;Uchibe K;Convente MR;Zhang D;Economides AN;Kaplan FS;Pacifici M;Iwamoto M;Shore EM
进行性骨化性纤维发育不良（FOP）是一种罕见且目前无法治愈的进行性骨外骨化的遗传性疾病，是人类异位骨化（HO）中最具致残性的形式，会导致骨骼畸形、运动障碍和过早死亡。大多数FOP患者在骨形态发生蛋白I型受体基因ACVR1R206H中存在激活突变，该突变促进异位软骨形成和骨生成，进而导致HO。我们之前表明，视黄酸受体γ（RARγ）激动剂帕洛伐汀在该疾病的损伤诱导型和遗传小鼠模型中能有效抑制HO。在此我们报告，利用一种携带经典FOP的人类ACVR1R206H突变的新型条件性敲入小鼠品系，该药物还能预防自发性HO。此外，当给予哺乳期母亲帕洛伐汀时，它能恢复长骨生长，维持生长板功能，并保护生长中的突变新生小鼠。重要的是，帕洛伐汀维持了关节、四肢和身体的运动，为其作为FOP治疗药物的全面治疗潜力提供了明确证据。
Fibrodysplasia Ossificans Progressiva (FOP) is 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 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.