Analyses of Molecular Mechanisms Involved in Pathogenesis of 0steoporosis

我们建立了成骨细胞和破骨细胞调控的分子基础。在骨吸收方面，产生了骨桥蛋白基因敲除小鼠(JBMR，1998)，下列研究表明，该分子是雌激素耗竭后快速骨吸收所必需的(美国国家科学院院刊，1999.，1999)。利用基因敲除小鼠研究骨形成机制，我们确定(1)Tab是响应BMP的骨形成的新抑制剂(Cell，2000)，(2)一种独特的Smad对CBFA基因表达的调节(《生物化学杂志》(JBC)1998)(3)维生素D调节LD的新机制，螺旋环状螺旋转录因子的负调控因子(JBC，1997)，(4)螺旋-环-螺旋转录因子，以及负责结缔组织基因调控的HMG因子(JBC，1997)(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(内分泌学，2000；J的内分泌学，2000)，骨中的Klotho表型可以通过病毒介导的Klotho表达来挽救(《基因医学杂志》，2000)机械应力是考虑骨质疏松治疗的最重要的方面之一，然而，机制尚未阐明。我们发现骨桥蛋白和klotho在去负荷的小鼠骨丢失中起着关键的作用和先决条件(《实验医学杂志》，2001)(《内分泌学杂志》，2001)。综上所述，我们的研究确定了骨量维持和丢失的关键分子，这些发现对于理解骨质疏松症的发病机制和考虑治疗骨质疏松症患者的措施具有重要意义。

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.