Angiotensin II accelerates osteoporosis by activating osteoclasts.
Recent clinical studies suggest that several antihypertensive drugs, especially angiotensin-converting enzyme inhibitors, reduced bone fractures. To clarify the relationship between hypertension and osteoporosis, we focused on the role of angiotensin II (Ang II) on bone metabolism. In bone marrow-derived mononuclear cells, Ang II (1x10(-6) M) significantly increased tartrate-resistant acid phosphatase (TRAP) -positive multinuclear osteoclasts. Of importance, Ang II significantly induced the expression of receptor activator of NF-kappaB ligand (RANKL) in osteoblasts, leading to the activation of osteoclasts, whereas these effects were completely blocked by an Ang II type 1 receptor blockade (olmesartan) and mitogen-activated protein kinase kinase inhibitors. In a rat ovariectomy model of estrogen deficiency, administration of Ang II (200 ng/kg/min) accelerated the increase in TRAP activity, accompanied by a significant decrease in bone density and an increase in urinary deoxypyridinoline. In hypertensive rats, treatment with olmesartan attenuated the ovariectomy-induced decrease in bone density and increase in TRAP activity and urinary deoxypyridinoline. Furthermore, in wild-type mice ovariectomy with five-sixths nephrectomy decreased bone volume by microcomputed tomography, whereas these change was not detect in Ang II type 1a receptor-deficient mice. Overall, Ang II accelerates osteoporosis by activating osteoclasts via RANKL induction. Blockade of Ang II might become a novel therapeutic approach to prevent osteoporosis in hypertensive patients.
Shimizu
Hideo
H
Division of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nakagami
Hironori
H
Osako
Mariana Kiomy
MK
Hanayama
Rie
R
Kunugiza
Yasuo
Y
Kizawa
Takuji
T
Tomita
Tetsuya
T
Yoshikawa
Hideki
H
Ogihara
Toshio
T
Morishita
Ryuichi
R
D000135:Acid Phosphatase / Q000378:metabolism; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology*; D010024:Osteoporosis / Q000139:chemically induced*; D053244:Osteoprotegerin / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053244:Osteoprotegerin; D053245:RANK Ligand; D000804:Angiotensin II; D000135:Acid Phosphatase