脂联素通过调节OPG/RANKL系统对低出生体重大鼠成年期骨质疏松症的影响及机制研究

Osteoporosis is a common skeletal disease. It brings high burdens to families and society because its high risk of fracture and disability. Barker's hypothesis, also called thrifty phenotype hypothesis says that reduced fetal growth is strongly associated with a number of chronic conditions later in life, which includes osteoporosis. The development of bone is dynamic process. Nowadays, the studies main focused on menopausal women or old men, and ovariectomized rats in animal models. Here our study intends to study the mechanism of osteoporosis from the origin of life, and study the developing of osteoporosis. . OPG (Osteoprotegerin)/RANKL (receptor activator of nuclear factor - kB ligand) system is considered to be an important mechanism for osteoporosis. So, here we want to study the relation between bone development and OPG/RANKL.The study of adiponectin (APN) mainly focused on metabolic syndrome, but studies have found that APN was correlated with osteoporosis. Our preliminary research shows that first, APN was positively correlated to bone sound of speed in preterm infant; second, changes of bone microstructure like thinner Tb.Th(Trabecular thickness) and increased Tb.Sp Tb.Pf(Trabecular bone pattern factor) existed in intrauterine growth retardation(IUGR) rats rats of puberty and the abnormal disappeared in early adulthood, which suggested that effects of IUGR on bone development may persist for a long time after birth; third, the OPG and OPG/RANKL is lower in low birth weight rats than the normal ones, while the RANKL is higher. Here, we speculated that APN can influence the developing of bone though OPG/RANKL system, by inhibiting the expression of OPG and up-regulation that of RANKL.. So, here we had the low birth weight birth though the diet intervention of pregnancy rats, and monitor the growth of bone through the bone metabolism value, and the morphogenesis change. And we also study the relation between APN and OPG/RANKL, in order to know the mechanism of osteoporosis.

骨质疏松症是一种常见的全身性骨骼疾病，“Barker 假说”认为成年期慢性疾病与宫内营养不良有关，且骨的发育是个动态过程。目前关于骨质疏松症的研究多针对绝经期妇女或老年男性，动物模型多采用去卵巢大鼠模型，因而该研究进行低出生体重仔鼠造模，拟从生命起源开始动态探究骨质疏松症的发生。OPG（骨保护素）/RANKL（核转录因子kB受体活化素配体）系统被认为是骨质疏松症发生的一个重要机制，本研究拟从生命早期监测骨发育与OPG/RANKL的关系。有研究认为APN（脂联素）与骨质疏松症的发生之间存在相关关系，本课题组前期临床研究显示APN与骨密度呈正相关，动物实验显示低出生体重大鼠发育至青春期存在骨结构改变，且低出生体重仔鼠存在OPG/RANKL系统改变，因而本研究拟证实APN通过作用于OPG/RANKL系统于生命早期对骨代谢进行程序性调控，而这一调控过程可能是成年期骨质疏松症的发生原因。

骨质疏松症是一种常见的全身性骨骼疾病，数据显示，骨质疏松症现已跃居全球常见病、多发病的第七位，全球约有2亿人患有骨质疏松症。因而，研究骨质疏松症的发生机制对于防治骨质疏松症的发生、减少家庭及社会的负担具有重大意义。“Barker 假说”认为成年期慢性疾病与宫内营养不良有关，且骨的发育是个动态过程。目前关于骨质疏松症的研究多针对绝经期妇女或老年男性，动物模型多采用去卵巢大鼠模型，因而本该研究进行低出生体重仔鼠造模，拟从生命起源开始动态探究骨质疏松症的发生。OPG（骨保护素）/RANKL（核转录因子kB受体活化素配体）系统被认为是骨质疏松症发生的一个重要机制，因而本研究拟从生命早期监测骨发育与OPG/RANKL的关系。有研究认为APN（脂联素）与骨质疏松症的发生之间存在相关关系。. 本研究通过母孕期低蛋白饮食成功进行低出生体重仔鼠造模，microCT结果显示低出生体重仔鼠在12w龄骨量低于正常组，且骨小梁的结构更加疏松，提示低出生体重仔鼠较正常组更易出现骨质疏松。除第1w低出生体重仔鼠APN明显上升，其余时间点低出生体重组仔鼠APN水平均低于正常组。结合骨钙素（OC）和TRACP-5b（抗酒石酸酸性磷酸酶）的改变提示在低出生体重组的骨转换更加活跃，而这一骨转换的活跃则可能促进骨质疏松症的发生。. 在低出生体重仔鼠，在各时间点低出生体重组的OPG均高于正常（p<0.05），而RANKL均低于正常组（p<0.05），OPG/RANKL比值（第8w除外）亦高于正常组（p<0.05）。. 通过低出生体重仔鼠进行成骨细胞、破骨细胞的分离及培养，采用经不同浓度APN对成骨细胞、破骨细胞分别进行干预，发现APN量的增加，成骨细胞OPG mRNA表达下降、RANKL mRNA增加；而破骨细胞OPG mRNA表达上升、RANKL mRNA表达减少。提示APN通过作用于OPG/RANKL系统于生命早期对骨代谢进行程序性调控，而这一调控过程可能是成年期骨质疏松症的发生原因。