PDCD4调控成骨细胞凋亡及骨微环境改变在骨质疏松中的作用及机制研究

Osteoporosis is one of the most common age-related disease with high morbidity and risk of fracture. Accompanied by the aging society, osteoporosis has been a serious public health problem. Estrogen play an important role in the balance of osteogenesis and bone resorption, but the definite molecular mechanism is still unclear. We found that an apoptosis-related protein PDCD4 is regulated by the estrogen and highly expressed in osteoporosis. PDCD4 knockout mice was presented with higher bone mineral density and more bone trabecular. Further study showed that PDCD4 could regulate the expression of some osteogenic proteins, such as c-Src, Lim-1 and OPG. This process may be the key molecular mechanism about the etiology of estrogen related osteoporosis. Therefore, next we prepare to explore the molecular mechanism of the estrogen regulated PDCD4 in osteoblast apoptosis and osteoclast differentiation through the molecular, cellular experiments and the study of animal model. And the special role of PDCD4 in the etiology of osteoporosis will be studied. In this research we could provide a new theory of the molecular mechanism in the etiology of osteoporosis, and further provide insight into the new drug target for the treatment of osteoporosis.

骨质疏松症是最常见的老年性疾病之一，其发病率高，易导致骨折等严重并发症，已成为老龄化社会严重的健康问题。雌激素对于维持骨形成和骨吸收的平衡具有极其重要的作用，但是目前对于其分子机制研究尚不明确。本课题组前期的研究发现，一种凋亡相关蛋白PDCD4受雌激素的调控，并在骨质疏松患者中呈高表达，敲除PDCD4的转基因鼠表现为骨密度增高、骨小梁数量增多。进一步研究发现，PDCD4可调控c-Src、Lim-1、OPG等骨相关蛋白表达，这可能是调控雌激素相关骨质疏松发生的关键分子机制。以此为基础，本项目拟从分子、细胞水平结合动物模型在体实验，重点研究雌激素调控PDCD4在成骨细胞凋亡和破骨细胞分化中的分子机制，并进一步探讨PDCD4对骨质疏松症发病的重要作用。本项目不仅可以为骨质疏松症病因学研究提供重要的分子机制基础，还可以为其治疗提供新的理论依据及分子靶点。

伴随着世界人口老龄化，骨质疏松症的发病率日趋增加。但迄今尚缺乏明确的发病机制研究及治疗靶点，骨质疏松症的治疗日趋成为一个世界性的难题。我们利用基因芯片及大量标本验证发现凋亡相关蛋白PDCD4表达受雌激素调控，通过构建PDCD4基因敲除鼠及对其进行骨相关检测及分析，我们发现PDCD4可以影响成骨细胞凋亡、分化与矿化，以及破骨细胞分化等多个骨重塑过程，可能在雌激素相关骨质疏松发生方面起重要作用。本研究在大量前期工作的基础上从分子、细胞及动物水平阐明PDCD4对雌激素相关骨质疏松的调控作用及分子机制，揭示PDCD4介导骨质疏松症发病的分子机制，对骨质疏松症的预防及治疗提供新的理论依据及分子靶点。