Bone mineral density from early to middle adulthood in persons with Down syndrome

Tang, Joey; Luo, Hai‐Bin; Wong, Gloria H Y; Lau, M. M. Y.; Joe, G. M.; Tse, Michael; Ip, Patrick; Wong, Ian C. K.; Lum, Terry Yat Sang

doi:10.1111/jir.12608

Cited by 15 publications

(11 citation statements)

References 43 publications

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“…These skeletal deficits are caused by trisomy 21 (Ts21), also the most common cause of congenital cognitive impairment that occurs in about 1/700-1000 live births [3][4][5]. Unlike osteoporosis in individuals without DS, bone disorders in individuals with Ts21 arise due to developmental deficits at critical times of bone mass accretion and may be compounded by subsequent age-related bone loss [6][7][8][9]. Increased average lifespan in individuals with DS [10][11][12] has made the development and advancement of bone disease a concern for older individuals with Ts21 [6][7][8]13,14].…”

Section: Introduction 1skeletal Abnormalities In Dsmentioning

confidence: 99%

“…Unlike osteoporosis in individuals without DS, bone disorders in individuals with Ts21 arise due to developmental deficits at critical times of bone mass accretion and may be compounded by subsequent age-related bone loss [6][7][8][9]. Increased average lifespan in individuals with DS [10][11][12] has made the development and advancement of bone disease a concern for older individuals with Ts21 [6][7][8]13,14]. Humans with DS and mouse models of DS exhibit sexual dimorphic features in skeletal anomalies that include age, severity, and skeletal compartment [1,[15][16][17][18][19][20].…”

Section: Introduction 1skeletal Abnormalities In Dsmentioning

confidence: 99%

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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

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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.

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Section: Introduction 1skeletal Abnormalities In Dsmentioning

confidence: 99%

Section: Introduction 1skeletal Abnormalities In 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

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“…2017; Tang et al . 2019). In this setting, androgen deficiency appears to play a role in gender differences (Carfì et al .…”

Section: Discussionmentioning

confidence: 99%

Bone mineral density in adults with Down syndrome: a cross‐sectional study in a Brazilian sample

Fedrigo

Skare

Levandoski

et al. 2023

J intellect Disabil Res

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Background We aim to investigate the relationship between bone mass in a sample of Brazilian individuals with DS and handgrip strength, body mass index (BMI) and physical exercise. Methods Dual-energy X-ray emission densitometry analysis of bone mass in 26 individuals with DS (8 men and 18 women with a mean age of 30.7 ± 10.3 years) was conducted. Additionally, weight and height were measured to determine BMI, palmar grip strength was measured using a Jammar dynamometer®, and physical activity was classified using the International Physical Activity Questionnaire (IPAQ). Results In this sample, 2/15 (13.3%) individuals with age between 18 to 29 years had low BMD in the spine; 2/8 (25%) of those with age between 30 and 39 years also had low BMD in the spine and 2/3 (66.6%) with age ≥40 had low BMD in the femur. There were significant correlations between palmar grip strength and Z femoral neck score in women (P = 0.02) and between BMI and Z femoral neck score in men (P = 0.04). All other correlations lacked statistical significance (P > 0.05). Conclusions Brazilian patients with DS showed a high prevalence of low bone mass. Traditional factors such as muscle strength, BMI and physical activity appear to have little effect on bone mineral density in this population.

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“…Additionally, people with DS experience bone loss sooner and at a higher rate than the general population ( Carfì et al, 2017 ). Males with DS begin losing BMD in the femur much earlier than females with DS, suggesting a protective effect of the Hsa21 trisomy in the female biological sex in terms of maintaining BMD ( Carfì et al, 2017 ; Costa et al, 2017 , 2018 ; Tang et al, 2019 ). Lowered BMD is thought to be the product of dysregulated bone turnover and may be due to low bone formation, which has been shown in people with DS through serum biomarkers ( McKelvey et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice

Sloan

Thomas

Blackwell

et al. 2023

Disease Models &Amp; Mechanisms

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Down syndrome (DS) phenotypes result from triplicated genes, but it is generally unknown how specific three copy human chromosome 21 (Hsa21) orthologous genes or interactions between genes affect these traits. A mouse mapping panel genetically dissecting Hsa21 syntenic regions was used to investigate the contributions and interactions triplicated Hsa21 orthologous genes on mouse chromosome 16 (Mmu16). Four-month-old femurs of male and female Dp9Tyb, Dp2Tyb, Dp3Tyb, Dp4Tyb, Dp5Tyb, Dp6Tyb, Ts1Rhr, and Dp1Tyb;Dyrk1a+/+/- mice were analyzed by micro-computed tomography and 3-point bending to assess skeletal structure and mechanical properties. Male and female Dp1Tyb mice, with the entire Hsa21 homologous region of Mmu16 in three copies, display specific bone deficits similar to humans with DS and were used as a baseline comparison for the other strains in the panel. Bone phenotypes varied based on triplicated gene content, sex, and bone compartment. Three copies of Dyrk1a played a sex-specific, essential role in trabecular deficits and may interact with other genes to influence cortical deficits related to DS. Triplicated genes in Dp9Tyb and Dp2Tyb mice improved some skeletal deficits. As triplicated genes may both improve and worsen bone deficits, it is important to understand the interaction between and molecular mechanisms of skeletal alterations affected by these genes.

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Bone mineral density from early to middle adulthood in persons with Down syndrome

Cited by 15 publications

References 43 publications

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

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

Bone mineral density in adults with Down syndrome: a cross‐sectional study in a Brazilian sample

Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice

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