Gallagher A, Chambers T J, Tobias J H
Department of Histopathology, St. George's Hospital Medical School, London, United Kingdom.
Endocrinology. 1993 Dec;133(6):2787-91. doi: 10.1210/endo.133.6.8243306.
Although estrogen is thought to protect the skeleton by inhibiting bone resorption, we have also found that in the rat, estrogen stimulates cancellous bone formation. However, the extent to which the various skeletal actions of estrogen are mediated by classical estrogen receptors remains unclear. Although estrogen receptor antagonists such as tamoxifen have been used to study this question, interpretation of the results is complicated by the fact that this agent also acts as a partial estrogen agonist. However, the recent development of estrogen antagonists devoid of agonist activity provides an opportunity to explore this question further. We, therefore, investigated the effect of administration of the pure estrogen antagonist ICI 182,780 on the skeleton of adult female rats. We found that ICI 182,780 reduced bone volume at the proximal tibial metaphysis by approximately 30%, associated with an increase in osteoclast surface. We then investigated the effect of ICI 182,780 on the anabolic action of estrogen. We used ovariectomized rats treated with 3-amino-1-hydroxypropylidene-1-bisphosphonate to inhibit bone resorption, thereby preventing any increase in bone formation as a result of the stimulation of bone resorption due to estrogen deficiency. 17 beta-Estradiol (1 micrograms/kg) stimulated cancellous bone formation in such animals by approximately 8-fold; this increase was abolished when ICI 182,780 was also given. In contrast, ICI 182,780 affected neither longitudinal nor periosteal tibial growth in either intact animals or ovariectomized rats given estradiol or vehicle. We conclude that ICI 182,780 reduces cancellous bone volume in the rat by antagonizing estrogen's actions on bone formation and resorption, suggesting that these processes are both mediated by classical estrogen receptors.
尽管雌激素被认为通过抑制骨吸收来保护骨骼，但我们也发现，在大鼠中，雌激素会刺激松质骨形成。然而，雌激素的各种骨骼作用在多大程度上由经典雌激素受体介导仍不清楚。尽管诸如他莫昔芬等雌激素受体拮抗剂已被用于研究这个问题，但由于该药物还作为部分雌激素激动剂起作用，使得结果的解释变得复杂。然而，近期无激动剂活性的雌激素拮抗剂的研发为进一步探索这个问题提供了机会。因此，我们研究了给予纯雌激素拮抗剂ICI 182,780对成年雌性大鼠骨骼的影响。我们发现ICI 182,780使胫骨近端干骺端的骨体积减少了约30%，同时破骨细胞表面积增加。然后我们研究了ICI 182,780对雌激素合成代谢作用的影响。我们使用用3-氨基-1-羟基亚丙基-1-双膦酸盐处理的去卵巢大鼠来抑制骨吸收，从而防止由于雌激素缺乏导致的骨吸收刺激而引起的骨形成增加。17β-雌二醇（1微克/千克）使此类动物的松质骨形成增加了约8倍；当同时给予ICI 182,780时，这种增加被消除。相比之下，ICI 182,780对完整动物或给予雌二醇或赋形剂的去卵巢大鼠的胫骨纵向生长和骨膜生长均无影响。我们得出结论，ICI 182,780通过拮抗雌激素对骨形成和骨吸收的作用来减少大鼠的松质骨体积，这表明这些过程均由经典雌激素受体介导。
