ABSTRACT
Skeletal insufficiency affects all individuals with Down syndrome (DS) or Trisomy 21 (Ts21) and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30 when there were persistent trabecular and cortical deficits and Dyrk1a was trending overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with Ts21.
ABSTRACT
Down syndrome (DS) phenotypes result from triplicated genes, but the effects of three copy genes are not well known. A mouse mapping panel genetically dissecting human chromosome 21 (Hsa21) syntenic regions was used to investigate the contributions and interactions of triplicated Hsa21 orthologous genes on mouse chromosome 16 (Mmu16) on skeletal phenotypes. Skeletal structure and mechanical properties were assessed in femurs of male and female Dp9Tyb, Dp2Tyb, Dp3Tyb, Dp4Tyb, Dp5Tyb, Dp6Tyb, Ts1Rhr and Dp1Tyb;Dyrk1a+/+/- mice. Dp1Tyb mice, with the entire Hsa21 homologous region of Mmu16 triplicated, display bone deficits similar to those of humans with DS and served as a baseline for 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 parameters. As triplicated genes can both improve and worsen bone deficits, it is important to understand the interaction between and molecular mechanisms of skeletal alterations affected by these genes.
Subject(s)
Down Syndrome , Humans , Mice , Male , Female , Animals , Down Syndrome/genetics , Chromosomes, Human, Pair 21 , Disease Models, Animal , PhenotypeABSTRACT
Bone abnormalities affect all individuals with Down syndrome (DS) and are linked to abnormal expression of DYRK1A, a gene found in three copies in people with DS and Ts65Dn DS model mice. Previous work in Ts65Dn male mice demonstrated that both genetic normalization of Dyrk1a and treatment with ~9 mg/kg/day Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea and putative DYRK1A inhibitor, improved some skeletal deficits. Because EGCG treatment improved mostly trabecular skeletal deficits, we hypothesized that increasing EGCG treatment dosage and length of administration would positively affect both trabecular and cortical bone in Ts65Dn mice. Treatment of individuals with DS with green tea extract (GTE) containing EGCG also showed some weight loss in individuals with DS, and we hypothesized that weights would be affected in Ts65Dn mice after EGCG treatment. Treatment with ~20 mg/kg/day EGCG for seven weeks showed no improvements in male Ts65Dn trabecular bone and only limited improvements in cortical measures. Comparing skeletal analyses after ~20mg/kg/day EGCG treatment with previously published treatments with ~9, 50, and 200 mg/kg/day EGCG showed that increased dosage and treatment time increased cortical structural deficits leading to weaker appendicular bones in male mice. Weight was not affected by treatment in mice, except for those given a high dose of EGCG by oral gavage. These data indicate that high doses of EGCG, similar to those reported in some treatment studies of DS and other disorders, may impair long bone structure and strength. Skeletal phenotypes should be monitored when high doses of EGCG are administered therapeutically.
