Aβ蛋白促骨质疏松作用及其介导的破骨细胞-成骨细胞失平衡的机制研究

项目名称： Aβ蛋白促骨质疏松作用及其介导的破骨细胞-成骨细胞失平衡的机制研究

项目编号： No.81472122

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 戎利民

作者单位： 中山大学

项目金额： 72万元

中文摘要： 骨质疏松症严重危害老年健康，但发病机制仍不明确。研究证实Aβ蛋白(Aβ)与阿尔茨海默病等多种老年退行性疾病密切相关,但其与骨质疏松(OP)关系未明。申请人前期研究发现Aβ在OP患者及动物模型骨组织中高表达,其量与骨密度呈负相关,且Aβ在体外可显著激活破骨细胞导致骨溶解,提示Aβ与OP存在重要联系(BONE,2014)。预实验提示Aβ可能通过MAPK/NF-κB/钙离子通路激活破骨细胞,且可明显抑制成骨细胞生成及增殖。因此,Aβ可能在分子水平通过影响破骨-成骨细胞失平衡而导致OP。本项目拟首先增大临床样本量,进一步明确人体其他OP常见部位骨组织中Aβ表达量与骨密度的联系;并通过静脉给药，考察Aβ促进动物OP的发生情况;最后,体外深入研究Aβ对人破骨细胞激活以及对人成骨细胞分化、凋亡作用的分子机制,从而阐明Aβ通过影响破骨-成骨细胞失平衡导致OP的发病机制，也为开发潜在的抗OP药物提供新靶点。

中文关键词： 骨质疏松症；Aβ蛋白；破骨细胞；成骨细胞；细胞凋亡

英文摘要： Osteoporosis is a devastating disease having enormous health impacts, particularly considering the global shift towards an aging population. However,the pathogenesis underlying osteoporosis is still elusive. Many studies have proved that amyloid beta peptide (Aβ) was associated with multiple degenerative disorders, such as Alzheimer's disease. However, the relationship between Aβ and osteoporosis has not been well-established yet. Our published paper (BONE，2014) showed that Aβ was elevated remarkably in the osteoporotic bone tissues both from human and ovariectomized rats when compared with the age-/sex-matched controls. Moreover, the expression levels had a negative correlation with corresponding bone mineral density in patients. In addition, Aβ enhanced osteoclast function potently, leading to osteolysis. Furthermore, our preliminary study indicated that the activation effect of Aβ on osteoclast might be related to the MAPK/NF-κB/calcium signal pathways. In addition, Aβ could suppress osteoblast formation and proliferation, indicating that the promoting effect of Aβ on osteoporosis might associate with osteoclast-osteoblast imbalance. In this study, firstly, we will further collect more patient osteoporotic bone specimens from multiple parts of human bodies prone to suffering osteoporosis and examine the relationship between Aβ expression levels and bone mineral density. Moreover, we will examine the Aβ expression levels in different age groups of rats and observe whether Aβ can accelerate osteoporosis after intravenously injecting into OVX rat models and pre-sinile SD rats. Finally, we try to elucidate the underlying molecular mechanism associated with osteoclast activation for MAPK/NF-κB/calcium signal pathways, and with osteoblast differentiation and apoptosis after Aβ treatment. We hope our study will uncover some unknown causes about osteoporosis and thus leading to better prevention and treatment.

英文关键词： osteoporosis;amyloid beta peptide;osteoclast;osteoblast;apoptosis