Activation of Renin-Angiotensin System Induces Osteoporosis Independently of Hypertension
Activation of Renin-Angiotensin System Induces Osteoporosis Independently of Hypertension
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DOI：
10.1359/jbmr.081006
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发表时间：
2009-02-01
影响因子：
6.2
通讯作者：
Ikeda, Kyoji
中科院分区：
文献类型：
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作者：
Asaba, Yutaro;Ito, Masako;Ikeda, Kyoji
高血压和骨质疏松症是两种主要的年龄相关疾病，然而，这种合并症的潜在分子机制尚不清楚。肾素-血管紧张素系统（RAS）在血压控制中起着重要作用，是抗高血压药物的重要作用靶点。使用嵌合RAS模型的转基因THM（筑波高血压小鼠）表达的人肾素和人血管紧张素原基因，我们表明，在这项研究中，RAS的激活诱导高营业额骨质疏松症加速骨吸收。仅表达人肾素基因的转基因小鼠血压正常，但骨量较低，表明骨质疏松症的发生与高血压本身的发展无关。体外培养显示，血管紧张素II（AngII）作用于成骨细胞，而不是直接作用于破骨细胞前体细胞，并增加破骨细胞生成支持细胞因子RANKL和血管内皮生长因子（VEGF），从而刺激破骨细胞的形成。AT 2受体的敲除抑制了AngII活性，而AT 1受体的沉默矛盾地增强了它，这表明成骨细胞表面上的两个AngII受体之间的功能性相互作用。最后，用ACE抑制剂依那普利治疗THM小鼠，可改善骨质疏松和高血压，而用血管紧张素受体阻断剂氯沙坦（一种AT 1特异性药物）治疗则导致低骨量表型恶化。因此，阻断AngII的合成可能是骨质疏松症和高血压的有效治疗方法。特别是对于那些同时患有这两种疾病的人来说。
Hypertension and osteoporosis are two major age-related disorders however, the underlying molecular mechanism for this comorbidity is not known. The renin-angiotensin system (RAS) plays a central role in the control of blood pressure and has been all important target of antihypertensive drugs. Using a chimeric RAS model of transgenic THM (Tsukuba hypertensive mouse) expressing both the human renin and human angiotensinogen genes, we showed in this study that activation of RAS induces high turnover osteoporosis with accelerated bone resorption. Transgenic mice that express only the human renin gene were normotensive and yet exhibited a low bone mass, suggesting that osteoporosis occurs independently of the development of hypertension per se. Ex vivo cultures showed that angiotensin II (AngII) acted on osteoblasts and not directly on osteoclast precursor cells and increased osteoclastogenesis-supporting cytokines, RANKL and vascular endothelial growth factor (VEGF), thereby stimulating the formation of osteoclasts. Knockdown of AT2 receptor inhibited the AngII activity, whereas silencing of the AT1 receptor paradoxically enhanced it, suggesting a functional interaction between the two AngII receptors on the osteoblastic cell surface. Finally, treatment of THM mice with an ACE inhibitor, enalapril, improved osteoporosis and hypertension, whereas treatment with losartan, an angiotensin receptor blockers specific for AT1, resulted in exacerbation of the low bone mass phenotype. Thus, blocking the synthesis of AngII may be an effective treatment of osteoporosis and hypertension. especially for those afflicted with both conditions.