The effect of calcimimetic and phosphate overloading diet on the parathyroid function in the mice of primary hyperparathyroidism.

拟钙剂和磷酸盐超载饮食对原发性甲状旁腺功能亢进症小鼠甲状旁腺功能的影响。

• 批准号: 13671122
• 负责人: INABA Masaaki
• 金额: $ 2.11万
• 依托单位: OSAKA CITY UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671122/
• 关键词: parathyroid hormone; cyclin D1; calcimimetic; primary hyperparathyroidism; 大動脈石灰化; 食餌性リン負荷; cyclin D1癌遺伝子; 高回転骨; 副甲状腺機能亢進症; SPF化; リン負荷

Transgenic mice with parathyroid-targeted overexpression of the cyctin D1 oncogene, provided direct experimental evidence that the cyclin D1 could drive excessive parathyroid cell proliferation with secretory abnormality of parathyroid hormone (PTH), and then developed hyperparathyroidism. Actually, parathyroid glands were enlarged and accelerated BrdU uptake in 30 weeks old transgenic mice. The mice also showed hypercalcemia at the age of 36 weeks. To determine whether these abnormalities could suppress by stimulating calcium sensing receptor (CaR), calcimimetic KRN1493, the calcium sensing receptor antagonist, was administered to the mice. The single administration of 30 mg/kg BW of KRN1493 suppressed both serum calcium and PTH levels 2 hrs after the administration on wild type mice. The same dose of single administration was also performed on 60-80 weeks old transgenic mice. Serum calcium and PTH levels were lowered on low calcemic group (serum calcium < 12 mg/dl), but were not on high calcemic group (serum calcium > 12 mg/dl). Immunohistochemical analyses showed suppressed CaR expression on low calcemic group compared to high calcemic group, revealing that the expression of CaR seems to regulate the biochemical effect of calcimimetic on parathyroid cell.

在转基因小鼠中以甲状旁腺为靶点过表达cyclin D1癌基因，为cyclin D1可驱动甲状旁腺细胞过度增殖，导致甲状旁腺激素（PTH）分泌异常，进而发生甲状旁腺功能亢进提供了直接的实验证据。事实上，30周龄转基因小鼠的甲状旁腺增大，并加速了BrdU的摄取。小鼠在36周龄时也表现出高钙血症。为了确定这些异常是否可以通过刺激钙敏感受体（CaR）来抑制，向小鼠施用钙敏感受体拮抗剂拟钙KRN 1493。单次给予30 mg/kg BW的KRN 1493在对野生型小鼠给药后2小时抑制了血清钙和PTH水平。还对60-80周龄转基因小鼠进行相同剂量的单次给药。低钙组（血钙< 12 mg/dl）血钙和PTH水平降低，而高钙组（血钙> 12 mg/dl）血钙和PTH水平无明显变化。免疫组化分析显示低钙组的CaR表达较高钙组受抑制，提示CaR的表达可能调节拟钙剂对甲状旁腺细胞的生化作用。