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

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...

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Autores principales:	Jared R. Thomas, Kourtney Sloan, Kelsey Cave, Joseph M. Wallace, Randall J. Roper
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DYRK1A Down syndrome osteoblasts sexual dimorphism gene dosage skeletal abnormalities Genetics QH426-470
Acceso en línea:	https://doaj.org/article/812ce9a77ca94c54b2844ed968d62d18
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spelling	oai:doaj.org-article:812ce9a77ca94c54b2844ed968d62d182021-11-25T17:41:19ZSkeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts10.3390/genes121117292073-4425https://doaj.org/article/812ce9a77ca94c54b2844ed968d62d182021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1729https://doaj.org/toc/2073-4425Trisomy 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. <i>DYRK1A</i>, 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 <i>Dyrk1a</i> 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 <i>Dyrk1a</i> copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed <i>Dyrk1a</i> gene (Ts65Dn,<i>Dyrk1a</i><sup>fl/wt</sup>) were mated with male <i>Osx-Cre<sup>+</sup></i> (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced <i>Dyrk1a</i> copy number in mature osteoblasts in Ts65Dn,<i>Dyrk1a</i><sup>+/+/<i>Osx-Cre</i></sup> P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,<i>Dyrk1a</i><sup>+/+/+</sup> (3 copies of DYRK1A in osteoblasts) and Ts65Dn,<i>Dyrk1a</i><sup>+/+/<i>Osx-Cre</i></sup> (2 copies of <i>Dyrk1a</i> in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced <i>Dyrk1a</i> 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 <i>Dyrk1a</i> 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.Jared R. ThomasKourtney SloanKelsey CaveJoseph M. WallaceRandall J. RoperMDPI AGarticleDYRK1ADown syndromeosteoblastssexual dimorphismgene dosageskeletal abnormalitiesGeneticsQH426-470ENGenes, Vol 12, Iss 1729, p 1729 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DYRK1A Down syndrome osteoblasts sexual dimorphism gene dosage skeletal abnormalities Genetics QH426-470
spellingShingle	DYRK1A Down syndrome osteoblasts sexual dimorphism gene dosage skeletal abnormalities Genetics QH426-470 Jared R. Thomas Kourtney Sloan Kelsey Cave Joseph M. Wallace Randall J. Roper Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts
description	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. <i>DYRK1A</i>, 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 <i>Dyrk1a</i> 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 <i>Dyrk1a</i> copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed <i>Dyrk1a</i> gene (Ts65Dn,<i>Dyrk1a</i><sup>fl/wt</sup>) were mated with male <i>Osx-Cre<sup>+</sup></i> (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced <i>Dyrk1a</i> copy number in mature osteoblasts in Ts65Dn,<i>Dyrk1a</i><sup>+/+/<i>Osx-Cre</i></sup> P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,<i>Dyrk1a</i><sup>+/+/+</sup> (3 copies of DYRK1A in osteoblasts) and Ts65Dn,<i>Dyrk1a</i><sup>+/+/<i>Osx-Cre</i></sup> (2 copies of <i>Dyrk1a</i> in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced <i>Dyrk1a</i> 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 <i>Dyrk1a</i> 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.
format	article
author	Jared R. Thomas Kourtney Sloan Kelsey Cave Joseph M. Wallace Randall J. Roper
author_facet	Jared R. Thomas Kourtney Sloan Kelsey Cave Joseph M. Wallace Randall J. Roper
author_sort	Jared R. Thomas
title	Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts
title_short	Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts
title_full	Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts
title_fullStr	Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts
title_full_unstemmed	Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts
title_sort	skeletal deficits in male and female down syndrome model mice arise independent of normalized dyrk1a expression in osteoblasts
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/812ce9a77ca94c54b2844ed968d62d18
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Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts

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