Activation of Renin‐Angiotensin System Induces Osteoporosis Independently of Hypertension

• Published in: Journal of bone and mineral research Vol. 24; no. 2; pp. 241 - 250
• Main Authors: Asaba, Yutaro, Ito, Masako, Fumoto, Toshio, Watanabe, Ken, Fukuhara, Ryoji, Takeshita, Sunao, Nimura, Yuji, Ishida, Junji, Fukamizu, Akiyoshi, Ikeda, Kyoji
• Format: Journal Article
• Language: English
• Published: Washington, DC John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR) 01.02.2009; Wiley
• Subjects: Angiotensin II - pharmacology; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensinogen - genetics; Animals; Biological and medical sciences; Bone Remodeling - drug effects; bone resorption; Fundamental and applied biological sciences. Psychology; Humans; hypertension; Hypertension - complications; Hypertension - physiopathology; Mice; Osteoblasts - drug effects; Osteoblasts - metabolism; osteoclast; osteoporosis; Osteoporosis - chemically induced; Osteoporosis - complications; Osteoporosis - physiopathology; RANK Ligand - metabolism; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - metabolism; Renin - genetics; Renin-Angiotensin System - drug effects; renin‐angiotensin system; Skeleton and joints; Vascular Endothelial Growth Factor A - metabolism; Vertebrates: osteoarticular system, musculoskeletal system; Hypertension; Diseases of the osteoarticular system; bone resorption; Resorption; Cardiovascular disease; Activation; Osteoclast; Osteoarticular system; Osteoporosis; Vertebrata; Renin angiotensin system; Mammalia; Bone; renin-angiotensin system
• ISSN: 0884-0431; 1523-4681; 1523-4681
• DOI: 10.1359/jbmr.081006

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 an 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.