Evaluation of an estrogen receptor-β agonist in animal models of human disease
Evaluation of an estrogen receptor-β agonist in animal models of human disease
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DOI：
10.1210/en.2003-0550
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发表时间：
2003-10-01
期刊：
影响因子：
4.8
通讯作者：
Keith, JC
中科院分区：
文献类型：
--
作者：
Harris, HA;Albert, LM;Keith, JC
1996年，第二个雌激素受体(ER)的发现，称为ERbeta，在科学界引发了强烈的兴趣，想要发现它在调节雌激素作用中的作用。然而，尽管对这种受体的功能进行了6年多的研究，但它在调节雌激素作用中的生理作用仍然不清楚，也存在争议。我们已经开发了一系列高选择性的ERbeta激动剂，并在几种临床相关的人类疾病啮齿动物模型中表征了它们的活性。其中一种化合物ERB-041的活性在这里被报道。我们从这些研究中得出结论，ERβ不调节雌激素在大鼠骨骼上的骨保存活性，也不影响排卵或卵巢摘除引起的体重增加。此外，这些化合物是非子宫营养和非乳房营养的。然而，ERB-041在人类白细胞抗原B27转基因大鼠炎症性肠病模型和Lewis大鼠佐剂性关节炎模型中具有显著的有益效果。每天低至1毫克/公斤的口服剂量可逆转人类白细胞抗原-B27转基因大鼠的慢性腹泻，并显著提高结肠组织学疾病评分。在治疗性佐剂诱导的关节炎模型中，相同的剂量方案在10天内将关节评分从12(最大炎症)降低到1。滑膜炎和Mankin(关节软骨)的组织学评分也显著降低(50%-75%)。这些数据表明，ERbeta的一个功能可能是调节免疫反应，ERbeta选择性配体可能是治疗慢性肠道和关节炎症的有用药物。
The discovery of a second estrogen receptor (ER), called ERbeta, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERbeta and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERbeta does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as low as 1 mg/kg reverse the chronic diarrhea of HLA-B27 transgenic rats and dramatically improve histological disease scores in the colon. The same dosing regimen in the therapeutic adjuvant-induced arthritis model reduces joint scores from 12 (maximal inflammation) to 1 over a period of 10 d. Synovitis and Mankin (articular cartilage) histological scores are also significantly lowered (50-75%). These data suggest that one function of ERbeta may be to modulate the immune response, and that ERbeta-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.