Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States of America.
PLoS One. 2022 Feb 23;17(2):e0264254. doi: 10.1371/journal.pone.0264254. eCollection 2022.
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.
骨骼异常影响所有唐氏综合征（DS）患者，与 DYRK1A 基因的异常表达有关，该基因在三倍体 DS 患者和 Ts65Dn DS 模型小鼠中存在。之前在 Ts65Dn 雄性小鼠中的研究表明，Dyrk1a 的基因正常化和每天约 9mg/kg 的表没食子儿茶素没食子酸酯（EGCG）治疗，绿茶中主要的多酚类物质和潜在的 DYRK1A 抑制剂，可改善一些骨骼缺陷。由于 EGCG 治疗主要改善了小梁骨骼缺陷，我们假设增加 EGCG 治疗剂量和治疗时间会对 Ts65Dn 小鼠的小梁和皮质骨产生积极影响。用含有 EGCG 的绿茶提取物（GTE）治疗 DS 患者也显示 DS 患者体重减轻，我们假设 EGCG 治疗后 Ts65Dn 小鼠的体重会受到影响。用约 20mg/kg/天的 EGCG 治疗七周，并未改善雄性 Ts65Dn 小鼠的小梁骨，仅对皮质骨指标有一定的改善。将约 20mg/kg/天 EGCG 治疗后的骨骼分析与之前报道的约 9、50 和 200mg/kg/天 EGCG 治疗进行比较，结果表明，增加剂量和治疗时间会增加皮质结构缺陷，导致雄性小鼠四肢骨骼变弱。除了经口服灌胃给予高剂量 EGCG 的小鼠外，治疗对小鼠体重没有影响。这些数据表明，高剂量的 EGCG（类似于一些 DS 和其他疾病的治疗研究报告的剂量）可能会损害长骨结构和强度。当高剂量 EGCG 进行治疗时，应监测骨骼表型。
