Shapiro Jay R, Boskey Adele L, Doty Stephen B, Lukashova Lyudmila, Blue Mary E
Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA.
Hospital for Special Surgery, Mineralized Tissue Laboratory, 535 E 70th Street, New York, NY 10021, USA.
Bone. 2017 Jun;99:1-7. doi: 10.1016/j.bone.2017.03.040. Epub 2017 Mar 18.
Rett syndrome (RTT) is a neurodevelopmental disorder predominately affecting young females, caused by deficiency of the global transcriptional protein methyl CpG binding protein 2 (MeCP2). Osteoblasts express MeCP2 and girls with RTT experience early onset osteoporosis, decreased bone mass and an increased fracture risk. There is no defined treatment for osteoporosis associated with RTT. The present study evaluated the effects of zoledronic acid (ZA), a third generation nitrogen-containing bisphosphonate with primarily anti-osteoclastic activity, in a mouse model of MeCP2 deficiency. Mice received weekly injections of 20μg/kg ZA for six weeks. Due to the shortened lifespan of hemizygous male (Mecp2-null) mice, treatment began at 3weeks of age for this group and corresponding wildtype (WT) male mice. Treatment for heterozygous (HET) and WT female mice began at 8weeks of age. Micro-computed tomography (micro-CT) and dynamic analyses of bone turnover were performed. ZA treatment led to significant increases in bone volume fraction, number, connectivity density and apparent density of trabecular bone in all genotypes of mice. In contrast, cortical bone generally was unaffected by ZA injections. Parameters of bone turnover, including mineral apposition rate, labeled bone surface and bone formation rate decreased after treatment with ZA. Mecp2-null mice had reduced labeled bone surface and bone formation rate compared to WT male mice. The results indicate that ZA treatment significantly improved trabecular bone mass in a murine model of RTT with little effect on cortical bone.
雷特综合征（RTT）是一种主要影响年轻女性的神经发育障碍，由全局转录蛋白甲基CpG结合蛋白2（MeCP2）缺乏引起。成骨细胞表达MeCP2，患有RTT的女孩会出现早发性骨质疏松症、骨量减少和骨折风险增加。目前尚无针对与RTT相关的骨质疏松症的明确治疗方法。本研究评估了唑来膦酸（ZA），一种主要具有抗破骨细胞活性的第三代含氮双膦酸盐，在MeCP2缺乏小鼠模型中的作用。小鼠每周注射20μg/kg ZA，持续六周。由于半合子雄性（Mecp2基因敲除）小鼠寿命缩短，该组小鼠及相应的野生型（WT）雄性小鼠在3周龄时开始治疗。杂合子（HET）和WT雌性小鼠在8周龄时开始治疗。进行了微计算机断层扫描（micro-CT）和骨转换的动态分析。ZA治疗导致所有基因型小鼠的骨体积分数、数量、连接密度和小梁骨表观密度显著增加。相比之下，皮质骨一般不受ZA注射的影响。用ZA治疗后，骨转换参数，包括矿物质沉积率、标记骨表面和骨形成率降低。与WT雄性小鼠相比，Mecp2基因敲除小鼠的标记骨表面和骨形成率降低。结果表明，ZA治疗显著改善了RTT小鼠模型中的小梁骨量，而对皮质骨影响较小。
