Activation of renin-angiotensin system induces osteoporosis independently of hypertension.

Abstract

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.

• Authors: Yutaro Asaba, Masako Ito, Toshio Fumoto, Ken Watanabe, Ryoji Fukuhara, Sunao Takeshita, Yuji Nimura, Junji Ishida, Akiyoshi Fukamizu, Kyoji Ikeda
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 24 Issue 2 Pg. 241-50 (Feb 2009) ISSN: 1523-4681 [Electronic] United States
• PMID: 18847324 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 2 Receptor Blockers
• Angiotensin-Converting Enzyme Inhibitors
• RANK Ligand
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Vascular Endothelial Growth Factor A
• Angiotensinogen
• Angiotensin II
• Renin

Topics

• Angiotensin II (pharmacology)
• Angiotensin II Type 2 Receptor Blockers
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Angiotensinogen (genetics)
• Animals
• Bone Remodeling (drug effects)
• Humans
• Hypertension (complications, physiopathology)
• Mice
• Osteoblasts (drug effects, metabolism)
• Osteoporosis (chemically induced, complications, physiopathology)
• RANK Ligand (metabolism)
• Receptor, Angiotensin, Type 1 (metabolism)
• Receptor, Angiotensin, Type 2 (metabolism)
• Renin (genetics)
• Renin-Angiotensin System (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)