【作者】 张松；

【导师】 王四旺；

【作者基本信息】 第四军医大学 ， 生药学， 2009， 硕士

【摘要】 绝经后骨质疏松(Postmenopausal Osteoporosis, PMO)在骨质疏松(osteoporosis,OP)中占有相当大的比例,具有较高的发病率,严重影响中老年妇女的生活质量。较长时期以来,PMO的预防和治疗都以雌激素替代疗法(Hormone replacement therapy)为主。但是伴随HRT的长期使用不断出现的性腺肿瘤发病率增高等副作用使其应用受到质疑和限制。开发和研究选择性雌激素受体调节剂(SERMs)引起了人们极大的兴趣,很多SERMs(如他莫昔芬和雷洛昔芬)开始用于临床。但长期使用这些药物仍会出现一些不良反应,如他莫昔芬会增加子宫癌、潮热、血栓;雷洛昔芬除了存在恶心、潮热、头痛、乳房肿痛等常见副作用外,还会引起深静脉血栓栓塞,故不适用于有血管舒缩症状的绝经后妇女。因此,寻找选择性更好、作用更强、副作用更少的防治PMO药物是目前的研究热点。其中,染料木素(Gen)是重要的异黄酮类植物雌激素;它具有与雌激素类似结构和温和的雌激素样生物活性。体内外研究结果均显示染料木素具有明显骨保护作用,能够促进成骨细胞(Osteoblast ,OB)的增殖和分化;在动物模型上,染料木素能够有效地缓解去势引起的骨密度降低。甲状旁腺激素(Parathyroid hormone,PTH)是调节钙磷代谢、维持机体钙平衡的主要激素,其主要的靶器官是骨骼和肾脏,并且在肾和骨骼中呈高表达。研究发现PTH相关蛋白能有效地促进骨骼合成,并且PTH和PTH相关蛋白能作用于相同的受体,即PTH受体1。目前,有关PMO患者体内甲状旁腺激素受体1(Parathyroid hormone receptorⅠ,PTHR1)与正常者的比较研究尚未见报道。本实验采用去势法建立雌性大鼠骨质疏松模型,观察去势大鼠骨质疏松股骨生物力学和骨密度的改变,同时检测股骨中PTHR1基因和蛋白水平,首次探讨PTHR1对去势诱发骨质疏松影响的重要意义。并在此基础上,我们对各组大鼠给予大中小剂量染料木素干预,设立对照组并在基因和蛋白水平检测股骨中PTHR1的表达水平。研究证明染料木素组动物的PTHR1表达水平较模型组动物明显上调,这提示染料木素治疗PMO过程中,PTHR1受体可能是其中的一种作用途径。更多还原

【Abstract】 Postmenopausal osteoporosis (PMO) at the OP plays a large proportion of high morbidity and mortality in old women seriously affect the quality of life. A longer period of time, PMO prevention and treatment are hormone replacement therapy (HRT)-oriented. However,long-term use of HRT associated with the continuing occurrence of side effects of its application has been questioned and restrictions. Development and research of selective estrogen receptor modulators (SERMs) has aroused great interest, a lot of SERMs (such as tamoxifen and raloxifene) and for clinical. At the same time, long-term use of these drugs will still be some adverse reactions, such as: tamoxifen will increase uterine cancer, hot flashes, the incidence of thrombosis; raloxifene exists apart from nausea, hot flashes, headache, breast pain, such as regular side-effects, but also caused by deep venous thrombo-embolism, it does not apply to have vasomotor symptoms in postmenopausal women. Therefore , selectively researching better, stronger, fewer side-effects of drug prevention and treatment of PMO is to study one of the hotspots. One of the main categories is the one source of isoflavones plants. Genistein (Gen) is an important phytoestrogen. It has a similar structure estrogen and mild estrogen-like biological activity. In vivo and in vitro studies have shown that Gen has a bone protective effect, can promote the proliferation and differentiation of OB. In animal model, Gen can effectively alleviate the castration caused by reduced bone mineral density.Parathyroid hormone (PTH, Parathyroid hormone) regulate calcium metabolism, calcium balance to maintain the body’s main hormone, its main target organs are bone and kidney. And it showed high expression in bone. Study found that PTH-related protein can effectively promote bone synthesis, and PTH and PTH-related protein can act on the same receptor, namely PTH receptor 1. At present, the patient PMOP parathyroid hormone receptor 1 (PTHR1), compared with the normal existence of differences has not been reported.Firstly,we set up the experiment using ovariectomized female rat model of osteoporosis was observed in rats ovariectomized osteoporosis femur biomechanics and bone mineral density changes in femoral. Detect PTHR1 gene and protein level to explore the PTHR1 on castration-induced osteoporosis the importance of osteoporosis. And on this basis, we given doses of genistein to rats, the establishment of the control group,and at the level of gene and protein detection femur in the expression level of PTHR1. The results show that genistein group PTHR1 expression level is significantly increases, compared to the blank model group, which suggests that genistein treatment PTHR1 receptors are one of the possible ways at PMO process.更多还原