LaCombe Jonathan M, Sloan Kourtney, Thomas Jared R, Blackwell Matthew P, Crawford Isabella, Wallace Joseph M, Roper Randall J
Department of Biology, Indiana University-Indianapolis, IN, USA.
Labcorp Early Development Laboratories, Inc., Greenfield, IN, USA.
bioRxiv. 2024 May 26:2024.05.24.595804. doi: 10.1101/2024.05.24.595804.
Skeletal insufficiency affects all individuals with Down syndrome (DS) or Trisomy 21 (Ts21) and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and overexpression were transitory until postnatal day (P) 30 when there were persistent trabecular and cortical deficits and was trending overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic are important to find temporally specific treatment periods for bone and other phenotypes associated with Ts21.
骨骼发育不全影响所有唐氏综合征（DS）或21三体综合征（Ts21）患者，与正常发育个体相比，由于骨形成期缩短和峰值骨量提前达到，在整个发育过程中可能会改变骨强度。DS男性患者的四肢骨骼缺陷也比女性出现得更早。在雄性Ts65Dn DS模型小鼠的股骨中，皮质骨缺陷在整个发育过程中都很明显，但小梁骨缺陷和过表达在出生后第30天（P30）之前是暂时的，此时出现持续的小梁骨和皮质骨缺陷，并且有过表达的趋势。在P21开始使用一种所谓的DYRK1A抑制剂或通过基因手段纠正与DS相关的骨骼缺陷，在P30时无效，但通过种系正常化在P36时改善了雄性小鼠的骨骼结构。雌性Ts65Dn小鼠的小梁骨和皮质骨缺陷在P30时明显，但在P36时消退，这代表了周期性的发育性骨骼正常化，进而发展为更明显的骨骼缺陷。骨骼缺陷的性别依赖性差异以及三体性的延迟影响对于找到与Ts21相关的骨骼和其他表型的时间特异性治疗期很重要。
