Disruption of bone development and homeostasis by trisomy in Ts65Dn Down syndrome mice

Blazek, J; Gaddy, Anna; Meyer, Rachel; Roper, Randall J.; Li, Jiliang

doi:10.1016/j.bone.2010.09.028

Cited by 42 publications

(58 citation statements)

References 44 publications

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“…For skeletal parameters in DS mouse models, we and others have identified significant deficits in BMD, trabecular bone parameters (thickness, separation and number) and cortical bone measures in Ts65Dn mice compared to euploid control mice [17]. Significant deficits in mineral apposition rate (MAR), bone formation rate (BFR), and strength properties in trisomic mice compared to controls were also observed [17, 26, 27]. …”

Section: Introductionmentioning

confidence: 96%

“…The Ts(17 16 )65Dn (Ts65Dn) mouse model is the most extensively studied and widely used animal model of DS and captures several behavioral and skeletal defects that are seen in humans with DS [13, 17–20]. We and others have shown that Ts65Dn mice exhibit behavioral and functional neurological deficits, including a variety of deficits on learning and memory tasks [20, 21].…”

Section: Introductionmentioning

confidence: 99%

“…Ts65Dn mice show deficits in novel object recognition (NOR) and spontaneous alternation [6], show increased locomotor activity [22, 23], have deficits in the Morris water maze (MWM) place learning (using the hidden platform version) and (under some testing conditions) on the cued task of the visible platform version [20, 23, 24], have gait abnormalities [25] and motor coordination deficits [23]. For skeletal parameters in DS mouse models, we and others have identified significant deficits in BMD, trabecular bone parameters (thickness, separation and number) and cortical bone measures in Ts65Dn mice compared to euploid control mice [17]. Significant deficits in mineral apposition rate (MAR), bone formation rate (BFR), and strength properties in trisomic mice compared to controls were also observed [17, 26, 27].…”

Section: Introductionmentioning

confidence: 99%

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Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Stringer

Abeysekera

Thomas

et al. 2017

Physiology & Behavior

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Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2–3 mg per day (~40–60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4 mg/mL] or a water control, with treatments yielding average daily intakes of ~50 mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)—which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking—and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Stringer

Abeysekera

Thomas

et al. 2017

Physiology & Behavior

Self Cite

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“…For example, deficiencies in bone formation [Parsons et al, 2007; Blazek et al, 2011]; brachycephaly, reduced facial, and cranial vault dimensions [Richtsmeier et al, 2000, 2002; Hill et al, 2007], and reduced cerebellar volume and granule cell density [Baxter et al, 2000] have been found in humans with DS and in Ts65Dn mice. Additionally, effects on hippocampal-based behaviors [Reeves et al, 1995; Pennington et al, 2003], occurrence of hematopoietic disease in the presence of GATA1 mutations [Crispino, 2005], and many similar effects on gene expression levels [Gardiner et al, 2003] have been discovered in people with DS and in Ts65Dn mice.…”

Section: Introductionmentioning

confidence: 99%

Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice

Starbuck

Dutka

Ratliff

et al. 2014

American J of Med Genetics Pt A

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Trisomy 21 results in gene-dosage imbalance during embryogenesis and throughout life, ultimately causing multiple anomalies that contribute to the clinical manifestations of Down syndrome. Down syndrome is associated with manifestations of variable severity (e.g., heart anomalies, reduced growth, dental anomalies, shortened life-span). Craniofacial dysmorphology and cognitive dysfunction are consistently observed in all people with Down syndrome. Mouse models are useful for studying the effects of gene-dosage imbalance on development. We investigated quantitative changes in the skull and brain of the Dp(16) 1Yey Down syndrome mouse model and compared these mice to Ts65Dn and Ts1Cje mouse models. Three-dimensional microcomputed tomography images of Dp(16)1Yey and euploid mouse crania were morphometrically evaluated. Cerebellar cross-sectional area, Purkinje cell linear density, and granule cell density were evaluated relative to euploid littermates. Skulls of Dp(16)1Yey and Ts65Dn mice displayed similar changes in craniofacial morphology relative to their respective euploid littermates. Trisomy-based differences in brain morphology were also similar in Dp(16)1Yey and Ts65Dn mice. These results validate examination of the genetic basis for craniofacial and brain phenotypes in Dp(16)1Yey mice and suggest that they, like Ts65Dn mice, are valuable tools for modeling the effects of trisomy 21 on development.

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“…These same cells are then responsible for the maintenance of the skeleton during adulthood and aging [12]. The measurement of bone biochemical markers provides a path to understand the underlying bone physiology, yet such information is scarce in patients with DS [13]. …”

Section: Introductionmentioning

confidence: 99%

Low bone turnover and low bone density in a cohort of adults with Down syndrome

et al. 2012

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Summary Increased incidence of osteoporosis in Down syndrome has been reported, but etiology is not established. We report low bone turnover markers and bone mineral density (BMD) in a cohort of people with Down syndrome without consistent clinical risk factors. Our results should guide future studies and treatments for this common problem. Introduction To better understand the etiology for osteoporosis in Down syndrome (DS), we measured bone density by dual-energy X-ray absorptiometry (DXA) and circulating biochemical markers of bone formation and resorption in a cohort of 30 community-dwelling DS adults. Methods Seventeen males and 13 females followed in the University of Arkansas Down Syndrome Clinic were evaluated by DXA to estimate BMD and underwent phlebotomy to measure serum procollagen type-1 intact N-terminal propeptide (P1NP) to evaluate bone formation, and serum C-terminal peptide of type-I collagen (CTx) to evaluate bone resorption. Results Seven of 13 DS females and 12 of 17 DS males had low bone mass at one of measured sites (z≤−2.0). When data were grouped by age, males had apparent osteopenia earlier than females. The mean P1NP in the normal group was 19.2±5.2 ng/ml vs. 2.2±0.9 ng/ml in the DS group (P= 0.002). Serum CTx levels in the normal group were 0.4± 0.1 ng/ml vs. 0.3±0.1 ng/ml (P=0.369). Conclusions Low BMD in adults with DS is correlated with a significant decrease in bone formation markers, compared to controls without DS, and is independent of gender. These data suggest that diminished osteoblastic bone formation and inadequate accrual of bone mass, with no significant differences in bone resorption, are responsible for the low bone mass in DS. These observations question the use of antiresorptive therapy in this population and focus attention on increasing bone mass by other interventions.

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Disruption of bone development and homeostasis by trisomy in Ts65Dn Down syndrome mice

Cited by 42 publications

References 44 publications

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice

Low bone turnover and low bone density in a cohort of adults with Down syndrome

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