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Pathophysiological study on Osteoporosis using Osteopontin-Knock out mice

骨桥蛋白敲除小鼠骨质疏松症的病理生理学研究

基本信息

批准号：
10044246
负责人：
NODA Masaki
金额：
$ 6.21万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Osteopontin is produced by osteoblasts and osteoclasts, is one of the more abundant non-collagenous proteins in bone matrix. However, the significance of the presence of osteopontin in in vivo has not been known. In our experiments, osteopontin-deficient and wild-type mice, 4.5-6 months old, were ovariectomized, while control animals were subjected to sham surgeries. We found that osteopontin knockout mice are resistant to ovariectomy-induced bone resorption compared to wild-type mice. Micro-computed tomography analysis indicated significant reduction in bone volume by ovariectomy in wild-type mice while the osteopontin-deficient mice exhibited less reduction in trabecular bone volume after ovariectomy. Histomorphometrical analysis of these trabecular bones confirmed the results of the μCT, demonstrating a large reduction in bone volume following ovariectomy in the wild-type mice, but only a slight, non-significant reduction in the osteopontin-deficient mice. Bone formation rate was increased following ovariectomy in wild-type animals, as expected, but was it not affected in osteopontin-deficient mice. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells in the bones of wild-type animals was increased about three fold following ovariectomy, compared to sham-operated animals, while ovariectomy did not significantly increase the number of osteoclasts in osteopontin-deficient mice. Reduction in uterine weight was observed similarly in both wild-type and osteopontin-deficient mice indicating the specificity of the effect of osteopontin-deficiency on bone metabolism. We propose that osteopontin is essential for postmenopausal osteoporosis in women. Strategies to counteract osteopontin's action may prove effective in suppressing osteoporosis. These results confirm the resistance of the OPN-deficient mice to bone resorption following ovariectomy and established the importance of osteopontin in bone in osteoporosis and bone metabolism.

骨桥蛋白由成骨细胞和破骨细胞产生，是骨基质中含量较丰富的非胶原蛋白之一。然而，骨桥蛋白在体内存在的意义尚不清楚。在我们的实验中，4.5-6月龄的骨桥蛋白缺陷和野生型小鼠被切除卵巢，而对照组动物接受假手术。我们发现，与野生型小鼠相比，骨桥蛋白基因敲除小鼠对卵巢切除诱导的骨吸收具有抵抗力。显微计算机断层扫描分析显示，野生型小鼠去卵巢后骨体积显著减少，而骨桥蛋白缺陷小鼠去卵巢后骨小梁体积减少较少。对这些松质骨的组织形态计量学分析证实了μCT的结果，显示野生型小鼠去卵巢后骨体积大幅减少，但骨桥蛋白缺乏的小鼠只有轻微的、不明显的减少。正如预期的那样，野生型动物卵巢切除后骨形成率增加，但骨桥蛋白缺陷小鼠的骨形成速度没有受到影响。与假手术动物相比，去卵巢后野生型动物骨骼中抗酒石酸酸性磷酸酶(TRAP)阳性细胞的数量增加了约三倍，而去卵巢并没有显著增加骨桥蛋白缺陷小鼠的破骨细胞数量。在野生型和骨桥蛋白缺乏的小鼠中，子宫重量的减轻是相似的，这表明骨桥蛋白缺乏对骨骼代谢的影响具有特异性。我们认为骨桥蛋白对女性绝经后骨质疏松症是必不可少的。对抗骨桥蛋白作用的策略可能被证明在抑制骨质疏松症方面有效。这些结果证实了OPN缺陷小鼠对去卵巢后骨吸收的抵抗，并证实了骨桥蛋白在骨质疏松症和骨代谢中的重要性。