在唐氏综合征小鼠模型的发育过程中,出现与三体 Dyrk1a 相关的骨骼表型的性别特异性。

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-23 DOI:10.1242/dmm.050914
Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper
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引用次数: 0

摘要

骨骼发育不全会影响所有患有唐氏综合征(DS)或 21 三体综合征(Ts21)的个体,与发育正常的个体相比,由于骨骼形成期缩短和骨量峰值提前达到,骨骼发育不全可能会改变整个发育过程中的骨强度。患有 DS 的男性也会先于女性出现骨骼畸形。在雄性Ts65Dn DS模型小鼠的股骨中,皮质缺陷在整个发育过程中都很明显,但骨小梁缺陷和Dyrk1a过表达是暂时的,直到出生后第30天,才出现持续的骨小梁和皮质缺陷以及Dyrk1a过表达趋势。从 P21 开始,通过所谓的 DYRK1A 抑制剂或基因手段来纠正 DS 相关的骨骼缺陷,但在 P30 时效果不佳,但到 P36 时,Dyrk1a 的种系正常化改善了雄性的骨骼结构。雌性Ts65Dn小鼠的骨小梁和皮质缺陷在P30时很明显,但到P36时有所缓解,这是周期性骨骼发育正常化的典型表现,这种正常化会发展成更突出的骨骼缺陷。三体Dyrk1a的延迟影响导致骨骼缺陷的性别差异,这对于找到与Ts21相关的骨骼和其他表型的时间特异性治疗期非常重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model.

Skeletal insufficiency affects all individuals with Down syndrome (DS) or trisomy 21 and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to those in 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 Dyrk1a overexpression were transitory until postnatal day (P) 30, when there were persistent trabecular and cortical deficits and Dyrk1a was trending toward 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 Dyrk1a 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 Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with trisomy 21.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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