Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Genes (Basel). 2021 Oct 28;12(11):1729. doi: 10.3390/genes12111729.
Trisomy 21 (Ts21) causes alterations in skeletal development resulting in decreased bone mass, shortened stature and weaker bones in individuals with Down syndrome (DS). There is a sexual dimorphism in bone mineral density (BMD) deficits associated with DS with males displaying earlier deficits than females. The relationships between causative trisomic genes, cellular mechanisms, and influence of sex in DS skeletal abnormalities remain unknown. One hypothesis is that the low bone turnover phenotype observed in DS results from attenuated osteoblast function, contributing to impaired trabecular architecture, altered cortical geometry, and decreased mineralization. , found in three copies in humans with DS, Ts65Dn, and Dp1Tyb DS model mice, has been implicated in the development of postnatal skeletal phenotypes associated with DS. Reduced copy number of to euploid levels from conception in an otherwise trisomic Ts65Dn mice resulted in a rescue of appendicular bone deficits, suggesting DYRK1A contributes to skeletal development and homeostasis. We hypothesized that reduction of copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed gene (Ts65Dn,) were mated with male (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced copy number in mature osteoblasts in Ts65Dn, P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn, (3 copies of DYRK1A in osteoblasts) and Ts65Dn, (2 copies of in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced in osteoblasts. This suggests that trisomic DYRK1A does not affect osteoblast function in a cell-autonomous manner at or before P42. Although male Dp1Tyb and Ts65Dn mice exhibit similar skeletal deficits at P42 in both trabecular and cortical bone compartments between euploid and trisomic mice, female Ts65Dn mice exhibit significant cortical and trabecular deficits at P42, in contrast to an absence of genotype effect in female Dp1Tyb mice in trabecular bone. Taken together, these data suggest skeletal deficits in DS mouse models and are sex and age dependent, and influenced by strain effects, but are not solely caused by the overexpression of in osteoblasts. Identifying molecular and cellular mechanisms, disrupted by gene dosage imbalance, that are involved in the development of skeletal phenotypes associated with DS could help to design therapies to rescue skeletal deficiencies seen in DS.
21 三体（Ts21）导致骨骼发育异常，导致唐氏综合征（DS）患者骨量减少、身材矮小和骨骼脆弱。DS 患者的骨矿物质密度（BMD）缺陷存在性别二态性，男性的缺陷出现得比女性更早。导致三体的基因、细胞机制以及性别的关系在 DS 骨骼异常中仍不清楚。一种假设是，DS 中观察到的低骨转换表型是由于成骨细胞功能减弱导致的，这导致了小梁结构受损、皮质几何形状改变和矿化减少。在唐氏综合征患者中，三倍体的 DYRK1A 基因（在人类中发现），Ts65Dn 和 Dp1Tyb DS 模型小鼠，与 DS 相关的骨骼表型的发展有关。在其他三倍体 Ts65Dn 小鼠中，从概念上降低 拷贝数至正常二倍体水平，导致四肢骨骼缺陷得到挽救，这表明 DYRK1A 有助于骨骼发育和平衡。我们假设，降低三体成骨细胞中的 拷贝数将改善三体小鼠的细胞功能和骨骼结构异常。雌性 Ts65Dn 小鼠（带有 floxed 基因）与雄性 （在大约 E13.5 时开始在成骨细胞中表达）小鼠交配，导致成熟的 Ts65Dn 、P42 雄性和雌性三体和二倍体小鼠中的 拷贝数减少，与同窝对照相比。雄性和雌性 Ts65Dn 、（成骨细胞中的 3 个 DYRK1A 拷贝）和 Ts65Dn 、（成骨细胞中的 2 个 拷贝）在小梁结构和皮质几何形状上都表现出相似的缺陷，而在成骨细胞中减少 并没有改善。这表明，在 P42 或之前，三体 DYRK1A 不会以细胞自主性方式影响成骨细胞的功能。尽管 P42 时雄性 Dp1Tyb 和 Ts65Dn 小鼠在二倍体和三体小鼠的小梁和皮质骨骨腔之间都表现出相似的骨骼缺陷，但雌性 Ts65Dn 小鼠在 P42 时表现出明显的皮质和小梁缺陷，而雌性 Dp1Tyb 小鼠在小梁骨中没有表现出基因型效应。总之，这些数据表明 DS 小鼠模型中的骨骼缺陷是性别和年龄依赖性的，并受品系效应的影响，但不仅仅是由于成骨细胞中 基因的过度表达。确定因基因剂量失衡而中断的分子和细胞机制，这些机制与 DS 相关的骨骼表型的发展有关，这可能有助于设计治疗方案来挽救 DS 中所见的骨骼缺陷。
