Activation of renin-angiotensin system induces osteoporosis independently of hypertension.
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.
Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
Yutaro
Y
Asaba
Masako
M
Ito
Toshio
T
Fumoto
Ken
K
Watanabe
Ryoji
R
Fukuhara
Sunao
S
Takeshita
Yuji
Y
Nimura
Junji
J
Ishida
Akiyoshi
A
Fukamizu
Kyoji
K
Ikeda
D000804:Angiotensin II / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced* / Q000150:complications* / Q000503:physiopathology; D053245:RANK Ligand / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D053245:RANK Ligand; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin