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SERMs have substance-specific effects on bone, and these effects are mediated via ER alpha AF-1 in female mice

Artikel i vetenskaplig tidskrift
Författare Anna E Börjesson
Helen H. Farman
Sofia Movérare-Skrtic
Cecilia Engdahl
M. C. Antal
A. Koskela
J. Tuukkanen
Hans Carlsten
A. Krust
P. Chambon
Klara Sjögren
Marie K Lagerquist
Sara H Windahl
Claes Ohlsson
Publicerad i American Journal of Physiology-Endocrinology and Metabolism
Volym 310
Nummer/häfte 11
Sidor E912-E918
ISSN 0193-1849
Publiceringsår 2016
Publicerad vid Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning
Centre for Bone and Arthritis Research
Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition
Sidor E912-E918
Språk en
Länkar dx.doi.org/10.1152/ajpendo.00488.20...
Ämnesord estrogen receptor, estrogen, selective estrogen receptor modulators, mouse, osteoporosis, activation function-1 of estrogen receptor-alpha, estrogen-receptor-alpha, transcriptional activation functions, hormone, replacement therapy, cortical bone, postmenopausal women, fracture-toughness, serum estradiol, increased risk, breast-cancer, distal radius
Ämneskategorier Klinisk medicin, Endokrinologi

Sammanfattning

The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)alpha, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ER alpha AF-1 for the estradiol (E-2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ER alpha AF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ER alpha AF-1 (ER alpha AF-1(0)) with E-2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ER alpha AF-1(0) mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ER alpha AF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.

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