Prophylactic treatment of rapamycin ameliorates naturally developing and episode -induced heterotopic ossification in mice expressing human mutant ACVR1
Prophylactic treatment of rapamycin ameliorates naturally developing and episode -induced heterotopic ossification in mice expressing human mutant ACVR1
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DOI：
10.1186/s13023-020-01406-8
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发表时间：
2020-05-24
影响因子：
3.7
通讯作者：
Toguchida, Junya
中科院分区：
文献类型：
--
作者：
Maekawa, Hirotsugu;Kawai, Shunsuke;Toguchida, Junya
研究背景进行性骨化性纤维发育不良（Fibrodysplasia ossificans progressiva，FOP）是一种罕见的常染色体显性遗传疾病，其特征为软组织异位骨化（heterotopic ossification，HO），由ACVR 1A/ALK 2基因突变引起。激活素A是通过激活mTOR启动HO过程的关键分子，而mTOR抑制剂雷帕霉素可有效抑制激活素A诱导的HO。然而，很少有报道证实雷帕霉素对FOP的临床前景的影响。方法采用条件性表达人突变型ACVR 1A/ALK 2基因的小鼠，观察雷帕霉素对不同临床情况的作用。我们还比较了每种情况下早期治疗和发作启动治疗之间雷帕霉素的效果。结果连续、非发作依赖性给予雷帕霉素可降低FOP小鼠自然病程中HO的发生率和严重程度。夹伤不仅在损伤部位诱导HO，而且在对侧肢体也诱导HO，并引起炎症细胞中激活素A的长时间产生。虽然早期和损伤启动的雷帕霉素治疗抑制HO损伤部位，前者是更有效地防止HO在对侧肢体。雷帕霉素也能有效减少损伤诱导HO手术切除后复发HO的数量，早期治疗更有效。结论预防性治疗是雷帕霉素治疗FOP的一种有效方法。
Background Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease characterized by heterotopic ossification (HO) in soft tissues and caused by a mutation of the ACVR1A/ALK2 gene. Activin-A is a key molecule for initiating the process of HO via the activation of mTOR, while rapamycin, an mTOR inhibitor, effectively inhibits the Activin-A-induced HO. However, few reports have verified the effect of rapamycin on FOP in clinical perspectives. Methods We investigated the effect of rapamycin for different clinical situations by using mice conditionally expressing human mutant ACVR1A/ALK2 gene. We also compared the effect of rapamycin between early and episode-initiated treatments for each situation. Results Continuous, episode-independent administration of rapamycin reduced the incidence and severity of HO in the natural course of FOP mice. Pinch-injury induced HO not only at the injured sites, but also in the contralateral limbs and provoked a prolonged production of Activin-A in inflammatory cells. Although both early and injury-initiated treatment of rapamycin suppressed HO in the injured sites, the former was more effective at preventing HO in the contralateral limbs. Rapamycin was also effective at reducing the volume of recurrent HO after the surgical resection of injury-induced HO, for which the early treatment was more effective. Conclusion Our study suggested that prophylactic treatment will be a choice of method for the clinical application of rapamycin for FOP.