Huber C, Collishaw S, Mosley J R, Reeve J, Noble B S
Musculoskeletal Tissue Engineering Collaboration, Department of Medicine, University of Edinburgh, 49 Little France Crescent, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.
Calcif Tissue Int. 2007 Aug;81(2):139-44. doi: 10.1007/s00223-007-9049-6. Epub 2007 Jul 20.
Estrogens exert positive effects on the quantity and quality of bone, including the maintenance of osteocytes through the inhibition of their apoptosis. Ideally, selective estrogen receptor modulators (SERMs) confer all of the positive bone-associated effects of estrogens without any adverse effects. In a similar way to estrogen, the raloxifene analog LY 117018 has been shown to prevent bone loss in ovariectomized (OVX) rats. In this study, we investigated whether the osteocyte-sparing effect of 17beta-estradiol can be mimicked by the SERM LY 117018 in a rat model of OVX. Twenty-four juvenile female rats were divided into four treatment groups: sham-operated (SHAM), OVX, OVX + 17beta-estradiol (OVX+E(2)), and OVX + LY 117018 (OVX+SERM). At 7 or 14 days following the start of treatment, the radius and ulna were removed. The percentage of apoptotic osteocytes, determined using an in situ nick-translation method, was increased (2.5-fold at 7 days and sixfold at 14 days) in the OVX group compared with SHAM in both the radius and ulna. Treatment of OVX animals with either 17beta-estradiol at a dose rate of 0.125 mg/kg/day or LY 117018 at a dose rate of 3 mg/kg/day prevented these increases in osteocyte apoptosis similarly. These observations demonstrate that LY 117018 exerts a powerful inhibitory effect upon osteocyte apoptosis directly after estrogen loss, in a similar way to the known effect of 17beta-estradiol replacement. These results point to the potential benefits of SERMs on both the quantity and quality of bone in E(2)-depleted rats.
雌激素对骨骼的数量和质量具有积极作用，包括通过抑制骨细胞凋亡来维持骨细胞。理想情况下，选择性雌激素受体调节剂（SERM）能赋予雌激素所有与骨骼相关的积极作用，且无任何不良反应。与雌激素类似，雷洛昔芬类似物LY 117018已被证明可预防去卵巢（OVX）大鼠的骨质流失。在本研究中，我们调查了在OVX大鼠模型中，SERM LY 117018是否能模拟17β - 雌二醇对骨细胞的保护作用。将24只幼年雌性大鼠分为四个治疗组：假手术组（SHAM）、OVX组、OVX + 17β - 雌二醇组（OVX+E₂）和OVX + LY 117018组（OVX+SERM）。在治疗开始后的7天或14天，取出桡骨和尺骨。使用原位缺口平移法测定，OVX组桡骨和尺骨中凋亡骨细胞的百分比与SHAM组相比增加（7天时增加2.5倍，14天时增加6倍）。以0.125 mg/kg/天的剂量率用17β - 雌二醇或3 mg/kg/天的剂量率用LY 117018治疗OVX动物，同样能阻止骨细胞凋亡的这些增加。这些观察结果表明，LY 117018在雌激素缺乏后直接对骨细胞凋亡发挥强大的抑制作用，类似于17β - 雌二醇替代的已知作用。这些结果表明SERM对E₂缺乏大鼠骨骼的数量和质量具有潜在益处。
