Damien E, Price J S, Lanyon L E
Department of Veterinary Basic Sciences, The Royal Veterinary College, London, United Kingdom.
J Bone Miner Res. 1998 Aug;13(8):1275-82. doi: 10.1359/jbmr.1998.13.8.1275.
The estrogen receptor's role in bone cells' response to mechanical strain was investigated by studying the effect of the estrogen receptor modulators ICI 182, 780 and tamoxifen on the proliferation of primary cultures of rat long bone-derived osteoblasts stimulated by the independent and combined effects of 17beta-estradiol, mechanical strain, and the mitogens basic fibroblast growth factor (bFGF), truncated insulin-like growth factor (tIGF)-I and tIGF-II, and epidermal growth factor (EGF). 17Beta-estradiol (10(-10) M to 10(-8) M) increased [3H]thymidine incorporation equally in cells from males and females, as did a single period of cyclical strain in the plastic strips onto which the cells had been seeded (peak strain 3,400 microepsilon, 600 cycles, 1 Hz). At 10(-8) M, neither ICI 182,780 nor tamoxifen had any effect on basal [3H]thymidine incorporation in these cells, but both compounds prevented their proliferative responses to 10(-8) M 17beta-estradiol. Tamoxifen eliminated and ICI 182,780 substantially reduced the proliferation stimulated by strain. 17Beta-estradiol partially rescued the strain-related response from the effect of tamoxifen but not that of ICI 182,780. Both tamoxifen and ICI 182,780 reduced proliferation stimulated by 10(-8) M EGF but had no effect on that by 10(-7) M bFGF or tIGF-I and tIGF-II. That both ICI 182,780 and tamoxifen, which in other tissues act as estrogen antagonists, should reduce osteoblast proliferation stimulated by 17beta-estradiol and EGF, but not that by FGF or the IGFs, was expected since the mitogenic effects of estrogen and EGF involve the estrogen receptor, whereas those of FGF and the IGFs do not. That these compounds should prevent osteoblasts' proliferative response to strain suggests that strain also stimulates mitogenesis by a mechanism involving the estrogen receptor. If this is so, bones' reduced ability to maintain their structural strength after the menopause could be explained by less effective strain-related (re)modeling when estrogen is absent and, among other changes, the estrogen receptor could be down-regulated.
通过研究雌激素受体调节剂ICI 182,780和他莫昔芬对大鼠长骨来源的原代成骨细胞增殖的影响，来探讨雌激素受体在骨细胞对机械应变反应中的作用。这些成骨细胞受到17β-雌二醇、机械应变以及促有丝分裂原碱性成纤维细胞生长因子（bFGF）、截短的胰岛素样生长因子（tIGF）-I、tIGF-II和表皮生长因子（EGF）单独及联合作用的刺激。17β-雌二醇（10⁻¹⁰ M至10⁻⁸ M）使雄性和雌性细胞中的[³H]胸腺嘧啶核苷掺入量同等增加，细胞接种于其上的塑料条中的单个周期性应变（峰值应变3400微应变，600个周期，1赫兹）也有同样效果。在10⁻⁸ M浓度下，ICI 182,780和他莫昔芬对这些细胞的基础[³H]胸腺嘧啶核苷掺入均无影响，但两种化合物均能阻止细胞对10⁻⁸ M 17β-雌二醇的增殖反应。他莫昔芬消除了应变刺激的增殖反应，ICI 182,780则显著降低了该反应。17β-雌二醇部分挽救了他莫昔芬作用下与应变相关的反应，但不能挽救ICI 182,780作用下的反应。他莫昔芬和ICI 182,780均降低了10⁻⁸ M EGF刺激的增殖，但对10⁻⁷ M bFGF或tIGF-I及tIGF-II刺激的增殖无影响。ICI 182,780和他莫昔芬在其他组织中作为雌激素拮抗剂，它们能降低17β-雌二醇和EGF刺激的成骨细胞增殖，但不能降低FGF或IGF刺激的增殖，这是预期的，因为雌激素和EGF的促有丝分裂作用涉及雌激素受体，而FGF和IGF的促有丝分裂作用则不涉及。这些化合物能阻止成骨细胞对应变的增殖反应，这表明应变也通过一种涉及雌激素受体的机制刺激有丝分裂。如果是这样，绝经后骨骼维持其结构强度的能力下降可以解释为当雌激素缺乏时，与应变相关的（再）建模效果降低，并且除其他变化外，雌激素受体可能下调。
