Regulation of bone turnover by adjusting signal transduction

通过调节信号转导调节骨转换

基本信息

批准号：
07457346
负责人：
NAKAMURA Toshitka
金额：
$ 4.8万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

The results of the studies include items. The first, we clarified the changes in the bone mass, structure and mechanical properties of bone in the animal mode of osteoporosis using ovariectomized dogs and rats. Bisphosphonates blocked the osteoclastic bone resorption on the trabecular surface. The second, we investigated the abnormal bone remodeling induced by systemic inflammation using adjuvant arthritic rats model. We observed that indomathacin and methotrexate improved bone remodeling by reducing bone resorption in the animal model. Then, the third, we clarified the time-dependent changes in the bone remodeling after acute deprivation of estrogen in rats. The improvement of bone remodeling was observed by the administration of anti-human GP130 antibody which was known to inhibit the signal transduction of interleukin 6 and 11 in rat cells.The series of these studies indicated that the increase in bone resorption was critically important for the bone loss induced by ovariectomy and systemic inflammation with polyarthritis. The increases in the cytokine productions such as IL-1, IL-6, IL-11and tumor necrosis factors were suggested to be primary carses for the signals stimulating osteoclastgenesis in the bone marrow. In inflammation induced bone loss, activated T cells were suggested to responsible to increase these cytokines. In postovariectomy bone loss, estrogen deficiency was responsible to increase the cytokines in the bone marrow, inducing the development of osteoclasts. However, our results also indicated that the regulation of some specific cytokines by using antibody may not be able to completely maintain the mass and structure of bone in these osteoporosis models. The total regulation of bone resorption would be more potent than regulating some of the osteoclast-inducing cytokines in the treatment of osteoporosis.

研究结果包括项目。首先，我们利用去卵巢的狗和大鼠阐明了骨质疏松动物模型中骨量、骨结构和力学性能的变化。双磷酸盐阻断小梁表面的破骨细胞骨吸收。其次，我们使用佐剂关节炎大鼠模型研究了全身炎症引起的异常骨重塑。我们观察到吲哚美辛和甲氨蝶呤通过减少动物模型中的骨吸收来改善骨重塑。然后，第三，我们阐明了大鼠急性剥夺雌激素后骨重塑的时间依赖性变化。通过施用抗人 GP130 抗体观察到骨重塑的改善，该抗体已知可抑制大鼠细胞中白细胞介素 6 和 11 的信号转导。这一系列研究表明，骨吸收的增加对于骨重建至关重要。卵巢切除术和多关节炎全身炎症引起的骨质流失。 IL-1、IL-6、IL-11和肿瘤坏死因子等细胞因子产生的增加被认为是刺激骨髓中破骨细胞生成信号的主要因素。在炎症引起的骨质流失中，活化的 T 细胞被认为负责增加这些细胞因子。在卵巢切除术后骨质流失中，雌激素缺乏会增加骨髓中的细胞因子，诱导破骨细胞的发育。然而，我们的结果也表明，使用抗体调节某些特定细胞因子可能无法完全维持这些骨质疏松模型中的骨质量和结构。在骨质疏松症的治疗中，骨吸收的总体调节比调节一些破骨细胞诱导细胞因子更有效。