Davis Vicki L, Chan Chi-Chao, Schoen Timothy J, Couse John F, Chader Gerald J, Korach Kenneth S
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9427-32. doi: 10.1073/pnas.132247999. Epub 2002 Jun 24.
Despite the high prevalence of age-related cataracts, there are currently no known therapies to delay or prevent their occurrence. Studies in humans and rodent models suggest that estrogen may provide protection against age-related cataracts. The discovery of ocular estrogen receptors (ERs) indicates that estrogen protection may result from direct interactions with its receptors in the eye, instead an indirect consequence from effects on another tissue. Studies in our transgenic mouse model validate the concept that estrogen is beneficial for the eye. These mice express ER Delta , a dominant-negative form of ER alpha that inhibits ER alpha function. In the ER Delta 3 transgenic mice, cortical cataracts spontaneously form in ER Delta 3 females after puberty and progress with age. The cataracts initiate in the equatorial region of the lens where the epithelial cells differentiate into elongating fiber cells. Cataract formation can be prevented if the females are ovariectomized before, but not after, sexual maturity. Both male and female ER Delta 3 mice develop cataracts after neonatal treatment with the potent estrogen diethylstilbestrol (DES). The incidence of spontaneous and DES-induced cataracts in ER Delta 3 mice is 100%, yet these cataracts are absent from the wild-type mice. These data suggest that repression of estrogen action induces cortical cataract formation because estrogen is required to activate the ER Delta 3 repressor. Evidence of DES-induced cataracts in the ER Delta 3 males as well as the females suggests that estrogen is important in lens physiology in both sexes. The ER Delta 3 mice provide a powerful model for assessing the role of estrogen in maintaining the transparency of the lens.
尽管年龄相关性白内障的患病率很高，但目前尚无已知的疗法来延缓或预防其发生。在人类和啮齿动物模型中的研究表明，雌激素可能对年龄相关性白内障具有保护作用。眼部雌激素受体（ERs）的发现表明，雌激素的保护作用可能源于其与眼部受体的直接相互作用，而非对其他组织产生影响的间接结果。我们在转基因小鼠模型中的研究验证了雌激素对眼睛有益的这一概念。这些小鼠表达ER Delta，这是一种抑制ERα功能的ERα显性负性形式。在ER Delta 3转基因小鼠中，皮质性白内障在青春期后自发形成于ER Delta 3雌性小鼠中，并随年龄增长而进展。白内障始于晶状体的赤道区域，此处上皮细胞分化为伸长的纤维细胞。如果雌性小鼠在性成熟前而非性成熟后进行卵巢切除，则可预防白内障的形成。雄性和雌性ER Delta 3小鼠在新生期用强效雌激素己烯雌酚（DES）处理后都会发生白内障。ER Delta 3小鼠中自发性和DES诱导性白内障的发生率为100%，而野生型小鼠中则不存在这些白内障。这些数据表明，雌激素作用的抑制会诱导皮质性白内障的形成，因为激活ER Delta 3阻遏物需要雌激素。ER Delta 3雄性和雌性小鼠中DES诱导性白内障的证据表明，雌激素在两性晶状体生理中都很重要。ER Delta 3小鼠为评估雌激素在维持晶状体透明度中的作用提供了一个有力的模型。
