Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a
Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a
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DOI：
10.1093/hmg/ddv284
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发表时间：
2015-10-15
影响因子：
3.5
通讯作者：
Roper, Randall J.
中科院分区：
文献类型：
--
作者：
Blazek, Joshua D.;Abeysekera, Irushi;Roper, Randall J.
21三体导致唐氏综合征（DS）患者的骨骼改变，但致病的三体基因和拯救这些异常的治疗方法尚不清楚。患有退行性椎体滑移的个体表现出骨骼改变，包括骨矿物质密度降低、骨结构改变和独特的面部特征。由于外周骨骼异常和寿命延长，退行性椎体滑移患者越来越容易发生骨折。了解退行性椎体滑移骨骼异常的遗传和发育起源将促进治疗的发展，以挽救这些和其他与退行性椎体滑移相关的缺陷。DYRK1A在DS和Ts65Dn DS小鼠个体中有三个拷贝，并且被假设参与了包括骨骼异常在内的许多21三体表型。在Ts65Dn小鼠中，Dyrk1a拷贝数恢复到正常水平可以挽救阑尾骨异常，这表明适当水平的Dyrk1a表达对DS阑尾骨骼的发育和维持至关重要。使用DYRK1A抑制剂表没食子儿茶素-3-没食子酸酯治疗可改善Ts65Dn的骨骼表型。这些结果表明，通过靶向三体Dyrk1a，可能会在出生后挽救与退行性椎体变性相关的骨质减少表型。
Trisomy 21 causes skeletal alterations in individuals with Down syndrome (DS), but the causative trisomic gene and a therapeutic approach to rescue these abnormalities are unknown. Individuals with DS display skeletal alterations including reduced bone mineral density, modified bone structure and distinctive facial features. Due to peripheral skeletal anomalies and extended longevity, individuals with DS are increasingly more susceptible to bone fractures. Understanding the genetic and developmental origin of DS skeletal abnormalities would facilitate the development of therapies to rescue these and other deficiencies associated with DS. DYRK1A is found in three copies in individuals with DS and Ts65Dn DS mice and has been hypothesized to be involved in many Trisomy 21 phenotypes including skeletal abnormalities. Return of Dyrk1a copy number to normal levels in Ts65Dn mice rescued the appendicular bone abnormalities, suggesting that appropriate levels of DYRK1A expression are critical for the development and maintenance of the DS appendicular skeleton. Therapy using the DYRK1A inhibitor epigallocatechin-3-gallate improved Ts65Dn skeletal phenotypes. These outcomes suggest that the osteopenic phenotype associated with DS may be rescued postnatally by targeting trisomic Dyrk1a.