86 - Effects of Green Tea Extract EGCG on Humerus Bone Mineral Density over Development in the Ts65Dn down Syndrome Mouse Model

Poster Board Number: 86
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Abstract Body : Introduction and Objective: Down syndrome (DS) is a congenital disorder caused by trisomy of chromosome 21. This genetic imbalance alters the development and function of multiple body systems, including bone homeostasis. The dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) is a candidate gene for modulating DS skeletal phenotypes, and DYRK1A inhibitors such as epigallocatechin-3-gallate (EGCG) have shown potential to modulate bone development. However, the effects of EGCG as a therapeutic agent for skeletal development are not consistent, with results varying between studies. In this study, we longitudinally followed the evolution of humerus bone mineral density (BMD) in the Ts65Dn mouse model for DS to assess the effects of green tea extract (GTE)-EGCG treatment and its discontinuation.

Materials and Methods: We analysed 48 mice, which included 18 wild-type (WT) untreated, 12 WT treated, 9 trisomic (TS) untreated, and 9 TS treated mice. Treated mice received a chronic GTE-EGCG treatment of 30 mg/kg/day that started at embryonic day 9 and was maintained until 5 months (M) old. Afterwards, treatment was discontinued for at least 2 months. Micro-computed tomography (µCT) in vivo scans were performed four times over development to follow the BMD of the humerus: µCT1 at postnatal day (PD) 3 and µCT2 at PD29 in all mice; µCT3 at 5M in treated mice, and 6M in untreated mice; and µCT4 at 8M in all mice to assess treatment discontinuation. To calculate the BMD, we used the µCT images to obtain the average grey value of the humerus of each mouse and a calibration line based on the grey values corresponding to two known hydroxyapatite densities to extrapolate the BMD of each individual. Statistically significant differences in developmental trajectories were analysed with a mixed-effects model and differences between groups were evaluated using pairwise comparisons.

Results: Untreated WT and TS mice showed similar BMD over the period analysed, without significant differences. Chronic GTE-EGCG treatment significantly altered the developmental trajectory of humerus BMD in both WT (P< 0.0001) and TS treated mice (P=0.0023). At µCT1, WT and TS treated mice showed similar levels of BMD as compared to untreated mice, but tended to show lower BMD in µCT2, although these differences did not reach statistical significance. BMD reduction was rescued at µCT3, but at µCT4, both WT and TS treated mice showed a significant decline in BMD, probably as a rebound effect on bone turnover after a prolonged time of treatment administration.

Conclusion: Our results indicate that chronic treatment with GTE-EGCG from embryonic to adult stages alters bone development, causing a decrease earlier in postnatal development. Although BMD recover normal values in adulthood, it drops again with treatment discontinuation.

Significance: One comorbidity in DS is osteoporosis. According to our results, GTE-EGCG modulates BMD and could impact the appearance and progression of osteoporosis. Further research is needed to fully comprehend the variability of treatment responses depending on the developmental timing and its effects on skeletal development. This is crucial since GTE-EGCG is commercially accessible over-the-counter and can affect both the Down syndrome and the general population.