REGγ在骨质疏松中的调控作用及机制研究

Osteoporosis is the most common age-related diseases and it has been a social health probem accompanied by the aging society . The role of oxidative stress in osteoporosis is more important recently and high level ROS(Reactive Oxygen Species)which is caused by aging can produce oxidative stress and then induce osteoporosis. REGγ, a proteasome activator,was reported to be involved in pre-mature aging recently. Here we show that REGγ deficient mice had severe symptoms of osteoporosis and were sensitive to ROS associated with bone formation inhibition. In addition, We observed that REGγ upregulated the level of Foxo1 andβ-catenin in nucleus and We also detected that REGγ decreased PKAca,s protein level in cells. Furthernore,we found REGγ increased the expression of MnSOD in bone. Next,We will focus on the signaling pathway how REGγ regulate Foxo1/β-catenin, and then understand the program how MnSOD eliminate ROS to provide insight into the drug target in the treatment of osteoporosis.

骨质疏松症是最常见的老年性疾病之一，严重危害老年人的健康和生活质量。近年来，活性氧自由基（ROS）作为骨质疏松的一个危险因子逐渐受到重视，随着年龄的增加机体将产生大量的ROS，导致骨质疏松的发生。最新的研究表明，蛋白酶体激活因子 REGγ参与早衰的调控。本课题组在前期研究中发现， REGγ基因敲除小鼠出现严重的骨质疏松，对ROS敏感度增加以及成骨细胞生成骨能力下降的现象， 在细胞水平发现REGγ可以促进细胞核中Foxo1，β-catenin的表达，下调PKAca的表达，进一步发现REGγ上调小鼠组织中Foxo1/β-catenin下游分子MnSOD的表达。以此为基础，本项目将在分子、细胞、组织水平重点探讨REGγ调控Foxo1/β-catenin的信号途径，明确此信号途径下游分子MnSOD清除ROS的转录程序，从而为治疗骨质疏松提供新的分子靶点和治疗途径。

REGγ是一种蛋白酶体激活因子，它激活20S蛋白酶体后，能够介导多种细胞周期调控蛋白（如p21,p19,p16）的降解，从而进一步对细胞周期和凋亡进行调控。骨质疏松症是最常见的老年性疾病之一，严重危害老年人的健康和生活质量。哺乳动物的骨骼一直处于一个更新的过程，一方面成骨细胞不断生成骨，另一方面，破骨细胞不断吸收骨，两者维持平衡。在本项目中，我们进一步研究了REGγ对骨发育的影响。主要研究内容：1）REGγ对成骨细胞分化的影响。2）REGγ对破骨细胞分化的影响。这些研究对进一步认识REGγ在骨质疏松中的调控机制有重要的意义。