Engdahl Cecilia, Jochems Caroline, Gustafsson Jan-Ake, van der Saag Paul T, Carlsten Hans, Lagerquist Marie K
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, 413 46 Gothenburg, Sweden.
J Endocrinol. 2009 Dec;203(3):349-56. doi: 10.1677/JOE-09-0012. Epub 2009 Sep 14.
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 (OE(2)) 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 OE(2), and both treatments resulted in increased luciferase activity in bone. As expected, OE(2) 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 OE(2). LY117018 and OE(2) treatment resulted in similar luciferase activation in thymus. However, only OE(2) 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.
雷洛昔芬是一种具有组织特异性作用的选择性雌激素受体调节剂。雷洛昔芬作用背后的机制部分尚不清楚，本研究的目的是调查雷洛昔芬是否能在体内激活三个已知的雌激素反应器官（子宫，生殖器官；骨骼，非生殖器官；胸腺，免疫器官）中的经典雌激素信号通路。为此，我们使用了在雌激素反应元件（ERE）控制下带有荧光素酶基因的报告基因小鼠，从而能够通过经典雌激素途径检测体内基因转录的激活情况。对三个月大的去卵巢ERE-荧光素酶小鼠用雷洛昔芬类似物（LY117018）、雌二醇（OE(2)）或赋形剂处理3周。测量骨骼、子宫和胸腺中的荧光素酶激活情况，并与骨参数以及子宫和胸腺重量进行比较。雷洛昔芬类似物对骨矿物质密度（BMD）的影响程度与OE(2)相同，两种处理均导致骨骼中荧光素酶活性增加。正如预期的那样，OE(2)处理导致子宫重量增加和子宫荧光素酶活性增加，而LY117018对子宫重量和荧光素酶活性的影响较小，且明显低于OE(2)的影响。LY117018和OE(2)处理在胸腺中导致类似的荧光素酶激活。然而，只有OE(2)处理导致胸腺萎缩，而LY117018处理后未观察到对胸腺重量的影响。总之，雷洛昔芬类似物LY117018可在体内激活骨骼、子宫和胸腺中的经典雌激素途径，这种激活与BMD和子宫重量相关，但与胸腺重量无关。
