Animal models of hyperfunctioning parathyroid diseases for drug development
Animal models of hyperfunctioning parathyroid diseases for drug development
复制标题
DOI：
10.1517/17460440903022743
复制
发表时间：
2009-06
影响因子：
6.3
通讯作者：
Y. Imanishi;M. Inaba;Takehisa Kawata;Y. Nishizawà
中科院分区：
文献类型：
--
作者：
Y. Imanishi;M. Inaba;Takehisa Kawata;Y. Nishizawà
背景：矿物质和骨代谢紊乱已被认为是慢性肾脏疾病（CKD）患者高死亡率的一个危险因素。高磷血症、维生素D代谢障碍和继发性甲状旁腺功能亢进症（SHPT）是这些患者提高死亡率的治疗靶点。CKD的动物模型是不可缺少的，5/6肾切除术产生的尿毒症大鼠是开发新的治疗药物最有用的动物模型之一。与维护性血液透析的CKD患者相比，尿毒症大鼠存在寿命短、继发性甲状旁腺功能异常严重程度较轻等局限性，因此期待开发新的模型动物。目的：综述甲状旁腺功能亢进的分子发病机制及甲状旁腺功能亢进动物模型在新疗法开发方面的应用。结论：经PTH-cyclin D1转基因的甲状旁腺靶向cyclin D1癌基因过表达的小鼠，不仅发生甲状旁腺细胞增生异常，而且发生生化甲状旁腺功能亢进，伴有骨特征性异常。小鼠表现出年龄依赖性的生化甲状旁腺功能亢进，这使得药物的测试更加精确。此外，在难治性SHPT患者中，小鼠出现甲状旁腺细胞增生，随后出现单克隆扩增。
Background: Disorders of mineral and bone metabolism have been implicated as a risk factor in the high mortality in patients with chronic kidney disease (CKD). Hyperphosphatemia, disorders of vitamin D metabolism and secondary hyperparathyroidism of uremia (SHPT) are therapeutic targets in these patients to improve the mortality. Animal models for CKD are indispensable and uremic rats produced by 5/6-nephrectomies are one of the most useful animal models for the development of new therapeutic agents. As there are limitations of uremic rats such as short lifespan and less severity of secondary hyperparathyroidism distinct from CKD patients on maintenance hemodialysis, the development of new model animals is expected. Objective: This review discusses the molecular pathogenesis of hyperfunctioning parathyroid diseases and the applications of animal models exhibiting hyperparathyroidisms in the aspect of the development of new therapeutics. Conclusion: PTH–cyclin D1 transgenic mice, with parathyroid-targeted overexpression of cyclin D1 oncogene, not only developed abnormal parathyroid cell proliferation but, notably, also developed biochemical hyperparathyroidism with characteristic abnormalities in bone. The mice exhibit age-dependent development of biochemical hyperparathyroidism, which enables testing of the drug precisely. In addition, the mice develop parathyroid cell hyperplasia, followed by monoclonal expansion, which is observed in refractory SHPT patients.