In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue

Autor: Marie K Lagerquist, Hans Carlsten, Paul T. van der Saag, Cecilia Engdahl, Jan-Ake Gustafsson, Caroline Jochems
Přispěvatelé: Hubrecht Institute for Developmental Biology and Stem Cell Research
Rok vydání: 2009
Předmět:
Zdroj: Journal of Endocrinology, 203(3), 349-356. Society for Endocrinology
ISSN: 1479-6805
0022-0795
DOI: 10.1677/joe-09-0012
Popis: Raloxifene is a selective oestrogen receptor modulator with tissue-specific effects. The mechanisms behind the effects of raloxifene are partly unclear, and the aim of the present study was to investigate whether raloxifene can activate the classical oestrogen-signalling pathway in vivo in three known oestrogen-responsive organs, uterus (reproductive organ), bone (non-reproductive organ) and thymus (immune organ). For this purpose, we have used reporter mice with a luciferase gene under control of oestrogen-responsive elements (EREs), enabling detection of in vivo activation of gene transcription via the classical oestrogen pathway. Three-month-old ovariectomized ERE-luciferase mice were treated with the raloxifene analogue (LY117018), oestradiol (OE2) or vehicle for 3 weeks. Luciferase activation was measured in bone, uterus and thymus, and compared to bone parameters, and uterus and thymus weights. The raloxifene analogue affected bone mineral density (BMD) to the same extent as OE2, and both treatments resulted in increased luciferase activity in bone. As expected, OE2 treatment resulted in increased uterus weight and increased uterine luciferase activity, while the effect of LY117018 on uterus weight and luciferase activity was modest and significantly lower than the effect of OE2. LY117018 and OE2 treatment resulted in similar luciferase activation in thymus. However, only OE2 treatment resulted in thymic atrophy, while no effect on thymus weight was seen after LY117018 treatment. In summary, the raloxifene analogue LY117018 can activate the classical oestrogen pathway in bone, uterus and thymus in vivo, and this activation is associated with BMD and uterus weight, but not thymus weight.
Databáze: OpenAIRE