Simvastatin induces estrogen receptor-alpha expression in bone, restores bone loss, and decreases ERα expression and uterine wet weight in ovariectomized rats.
We previously reported that simvastatin induces estrogen receptor-alpha (ERα) in murine bone marrow stromal cells in vitro. In this study, we investigated the effect of simvastatin on ERα expression in bone and uterus in ovariectomized (OVX) rats and evaluated bone mass, bone strength, and uterine wet weight. Three-month-old Sprague-Dawley female rats received OVX or sham operation. Six weeks later, the rats were treated orally with simvastatin (5 or 10 mg/kg/day), or intraperitoneally with 17-β-estradiol (E(2)) or a combination of simvastatin and E(2) for 6 weeks. Uterine wet weight, bone mineral density (BMD) of lumbar vertebrae, biomechanics of lumbar vertebrae, and induction of ERα expression in the bone and uterus were analyzed. The 6-week simvastatin treatment improved lumbar vertebral BMD and boosted biomechanical performance of the vertebral body compared to the OVX control, suggesting that simvastatin can treat osteoporosis caused by estrogen deficiency. More interestingly, simvastatin could increase ERα expression and synergy with estradiol in bone while antagonizing estradiol in the uterus, along with uterus atrophy and uterine wet weight decreases. In conclusion, these data suggest that simvastatin exert opposing modulatory effects on ERα expression on bone and uterus in ovariectomized rats, inducing ERα expression and synergy with estrogen to perform anabolic effects on the bones while decreasing E2 efficacy and uterine wet weight. This finding may be helpful to explain the mechanism of statin treatment in osteoporosis caused by estrogen deficiency.
Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China.
Xu
X
Li
Quan-Sheng
QS
Song
Jing-Ying
JY
Wang
Hui-jie
HJ
Leng
Zhong-Qiang
ZQ
Chen
Zhong-Jun
ZJ
Liu
Geng-Ting
GT
Dang
Chun-Li
CL
Song
D015502:Absorptiometry, Photon; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000473:pathology* / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
D047628:Estrogen Receptor alpha; D019821:Simvastatin