Thorndike E A, Turner A S
Department of Clinical Sciences, Colorado State University, Ft.Collins, CO 80523, USA.
Front Biosci. 1998 Apr 16;3:c17-26. doi: 10.2741/a260.
The purpose of this review is to discuss the use of the aged ovariectomized ewe as a cost-effective large animal model to study coronary artery disease (CAD), osteoporosis, osteoarthritis (OA), and oral bone loss--conditions seen after menopause. Earlier studies from our laboratory showed a significant decline in the bone mineral density (BMD) of the iliac crest following ovariectomy in sheep, while subsequent studies demonstrated decreased bone loss (measured by dual energy X-ray absorptiometry (DXA)) in the lumbar vertebrae following ovariectomy. We examined the effects of estrogen deficiency and estrogen therapy on the terminal aorta of the aged ovariectomized (OVX) ewes and demonstrated subintimal thickening in the distal aorta of animals that were estrogen deficient when compared to the control groups. A popular model to study OA is the knee joint of sheep following medial or lateral meniscus removal combined with exercise, but there is a need for an estrogen-deficient large animal model of OA to study articular cartilage changes occurring after menopause. We saw an effect of ovariectomy on the biomechanical properties (aggregate modulus and shear modulus) of articular cartilage. Estrogen deficiency had a detrimental effect on the articular cartilage of the knee even though the cartilage of the OVX animals appeared grossly normal. In another study, 13.5 months following ovariectomy, we found an increase in estrogen receptor binding capacity of the articular cartilage suggesting that articular cartilage is a sex-hormone sensitive tissue. There is intense interest in the correlation between systemic osteoporosis and bone loss of the mandible and maxilla. We studied mandibular bone loss in OVX sheep using DXA. The mean BMD of the OVX group versus sham and estradiol-treated animals was lower, indicating that systemic bone loss in OVX ewes may be accompanied by oral bone loss. Coronary artery disease, osteoporosis, osteoarthritis (OA) and oral bone loss all have a major impact on women's heath after menopause and we found that certain characteristics of these conditions can be reproduced in the skeletally mature or aged estrogen-deficient sheep. It is premature to promote the sheep as the only model to study estrogen deficiency and the many differences from small animal omnivores and non-human primates need to be overcome and a search for more economical models must continue. This model, however, may offer the opportunity to study postmenopausal conditions and the safety and efficacy of new therapeutic agents.
本综述的目的是讨论使用老年去卵巢母羊作为一种经济高效的大型动物模型，以研究冠状动脉疾病（CAD）、骨质疏松症、骨关节炎（OA）和口腔骨质流失——这些都是绝经后出现的情况。我们实验室早期的研究表明，绵羊去卵巢后髂嵴骨矿物质密度（BMD）显著下降，而随后的研究表明，去卵巢后腰椎骨丢失减少（通过双能X线吸收法（DXA）测量）。我们研究了雌激素缺乏和雌激素治疗对老年去卵巢（OVX）母羊终末主动脉的影响，并证明与对照组相比，雌激素缺乏动物的远端主动脉内膜下增厚。一种常用的研究OA的模型是切除内侧或外侧半月板并结合运动后的绵羊膝关节，但需要一种雌激素缺乏的大型动物OA模型来研究绝经后发生的关节软骨变化。我们观察到去卵巢对关节软骨生物力学特性（聚集模量和剪切模量）的影响。尽管OVX动物的软骨外观基本正常，但雌激素缺乏对膝关节软骨有不利影响。在另一项研究中，去卵巢13.5个月后，我们发现关节软骨的雌激素受体结合能力增加，这表明关节软骨是一种对性激素敏感的组织。人们对全身骨质疏松症与下颌骨和上颌骨骨质流失之间的相关性非常感兴趣。我们使用DXA研究了OVX绵羊的下颌骨丢失情况。OVX组与假手术组和雌二醇治疗组动物的平均BMD较低，表明OVX母羊的全身骨质流失可能伴有口腔骨质流失。冠状动脉疾病、骨质疏松症、骨关节炎（OA）和口腔骨质流失对绝经后女性健康都有重大影响，我们发现这些情况的某些特征可以在骨骼成熟或老年雌激素缺乏的绵羊中重现。将绵羊作为研究雌激素缺乏的唯一模型还为时过早，需要克服与小型杂食动物和非人类灵长类动物的许多差异，并且必须继续寻找更经济的模型。然而，这个模型可能提供研究绝经后情况以及新治疗药物安全性和有效性的机会。
