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Analyses of Molecular Mechanisms Involved in Pathogenesis of 0steoporosis

0骨质疏松症发病分子机制分析

基本信息

批准号：
09307034
负责人：
NODA Masaki
金额：
$ 25.79万
依托单位：
Tokyo Medical 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：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

We established the molecular bases of regulation ofosteoblasts as well as osteoclasts. With regard to bone resorption, osteopontin knock out mice were produced (JBMR, 1998) and the following study indicated that this molecule is required for rapid bone resorption after estrogen depletion (Proceedings of the National Academy of Sciences U.S.A., 1999., 1999).Bone formation mechanism was studied using knockout mice and we identified (1) Tab as a novel inhibitor of bone formation in response to BMP (Cell, 2000) , (2) a unique Smad regulation of Cbfa gene expression (Journal of Biological Chemistry (JBC) 1998)(3) a novel mechanism of vitamin D regulation of ld, a negative regulator of helix loop helix type transcription factor (JBC,1997) , (4) a positive type helix-loop-helix transcription factor, Scleraxis and an HMG factor to be responsible for connective tissue gene regulation (JBC,1997)(JBC,2000).We also identified that klotho gene is involved in the regulation of bone resorption activity by regulating osteoprotegerin (Endocrinology, 2000 ; J of Endocrinology, 2000), and the klotho phenotype in bone could be rescued by virus mediated klotho expression (Journal of Gene Medicine, 2000)Mechanical stress is one of the most important aspects in contemplating osteoporosis treatment, however, no mechanism has been clarified. We found that osteopontin and klotho play critical roles and prerequisite for the bone loss in the unloaded mice (Journal of Experimental Medicine, 2001)(J of Endocrinology, 2001).Over all our research identified key molecular players in the bone volume maintenance and loss and these findings are important in understanding the pathogenesis of osteoporosis and to contemplate measures to treat patients suffering from this disease which is one of the major health problems in the modern society.

我们建立了成骨细胞和破骨细胞调节的分子基础。关于骨吸收，产生了骨桥蛋白敲除小鼠（JBMR，1998），并且以下研究表明，该分子是雌激素耗尽后快速骨吸收所需的（Proceedings of the National Academy of Sciences U.S.A.，1999., 1999).利用基因敲除小鼠研究骨形成机制，我们发现：（1）Tab是一种新的BMP诱导骨形成的抑制剂（Cell，2000），（2）Cbfa基因表达的独特Smad调节（《生物化学杂志》（JBC）1998）（3）维生素D调节ld的新机制，ld是螺旋环螺旋型转录因子的负调节因子（JBC，1997），（4）正型螺旋-环-螺旋转录因子，Scleraxis和负责结缔组织基因调节的HMG因子（JBC，1997年）（JBC，2000）。我们还发现klotho基因通过调节骨保护素参与骨吸收活性的调节。（Endocrinology，2000 ; J of Endocrinology，2000），并且骨中的klotho表型可以通过病毒介导的klotho表达来挽救（Journal of Gene Medicine，2000）。机械应力是考虑骨质疏松症治疗的最重要方面之一，然而，尚未阐明机制。我们发现骨桥蛋白和klotho在无负荷小鼠的骨丢失中起着关键的作用和先决条件（Journal of Experimental Medicine，2001）（J of Endocrinology，（2001年）在我们所有的研究中，确定了骨体积维持和损失的关键分子参与者，这些发现对于理解骨质疏松症的发病机制和考虑治疗患有这种疾病的患者的措施非常重要，现代社会的主要健康问题之一。