Skeletal dynamics of Down syndrome: A developing perspective

LaCombe, Jonathan; Roper, Randall J.

doi:10.1016/j.bone.2019.115215

Cited by 32 publications

(31 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…People with DS are typically short in stature, have lower bone density and characteristic changes in craniofacial morphology, such as brachycephaly (front to back shortening of the skull), and increased body fat content ( Baptista et al, 2005 ; Costa et al, 2018 ; Gutierrez-Hervas et al, 2020 ; Korenberg et al, 1994 ; LaCombe and Roper, 2020 ; Vicente et al, 2020 ). X-ray analysis at 14 weeks of age showed that Dp1Tyb mice had shorter tibia and skulls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of skeletal structures showed that Dp1Tyb mice have reduced bone density, shorter tibia and altered craniofacial structures, in particular brachycephaly, all of which are typical of DS ( Baptista et al, 2005 ; Costa et al, 2018 ; Herrera et al, 2020 ; LaCombe and Roper, 2020 ; Vicente et al, 2020 ). In agreement with this, Dp1Tyb mice have shorter body and femur length ( Thomas et al, 2020 ), smaller crania and mandibles, mid-facial hypoplasia and cranial doming ( Toussaint et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes

Lana-Elola

Cater

Watson-Scales

et al. 2021

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish if this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes

Lana-Elola

Cater

Watson-Scales

et al. 2021

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…Although previous studies have long associated skeletal deficits with DS, it remains unclear how these alterations arise in individuals with Ts21 [1,[15][16][17][18][19]. Skeletal phenotypes associated with Ts21 are a consequence of impaired bone formation as exhibited by diminished bone accrual, early attainment of peak bone mass, abnormal mineralization, and low bone mineral density [1,2,[13][14][15]17,19,[21][22][23][24]. Men and women with DS displayed lower BMD in the femoral neck and lumbar spine much earlier than individuals without DS, with men exhibiting bone loss around 20 years of age, and females experience rapid decline in BMD around 40 years of age [6,7,14].…”

Section: Development Of Skeletal Abnormalities In Individuals With Dsmentioning

confidence: 99%

Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts

Thomas

Sloan

Cave

et al. 2021

Genes

Self Cite

View full text Add to dashboard Cite

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. DYRK1A, 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 Dyrk1a 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 Dyrk1a copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed Dyrk1a gene (Ts65Dn,Dyrk1afl/wt) were mated with male Osx-Cre+ (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced Dyrk1a copy number in mature osteoblasts in Ts65Dn,Dyrk1a+/+/Osx-Cre P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,Dyrk1a+/+/+ (3 copies of DYRK1A in osteoblasts) and Ts65Dn,Dyrk1a+/+/Osx-Cre (2 copies of Dyrk1a in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced Dyrk1a 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 Dyrk1a 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.

show abstract

“…People with DS are typically shorter in stature, have lower bone density and characteristic changes in craniofacial morphology, such as brachycephaly (front to back shortening of the skull), and increased body fat content [23][24][25][26][27][28] . X-ray analysis at 14 weeks of age showed that Dp1Tyb mice had shorter tibia and skulls (Fig.…”

Section: Dp1tyb Mice Have Altered Skeletal Developmentmentioning

confidence: 99%

“…Analysis of skeletal structures, showed that Dp1Tyb mice have reduced bone density, shorter tibia and altered craniofacial structures, in particular brachycephaly. All of these changes are seen in people with DS [23][24][25]28,60 . In agreement with this, Dp1Tyb mice have been reported to have shorter body and femur length 61 and similar craniofacial changes have been seen in the Dp1Yey mouse strain, which has an extra copy of the same genes as Dp1Tyb 62,63 ECG studies in people with DS without congenital heart defects showed increased Twave length, similar to that seen in Dp1Tyb mice 64 .…”

mentioning

confidence: 99%

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes

Lana-Elola

Cater

Watson-Scales

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

Skeletal dynamics of Down syndrome: A developing perspective

Cited by 32 publications

References 103 publications

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes

Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes

Contact Info

Product

Resources

About