SEX HORMONE EFFECTS ON CARTILAGE AND BONE

骨关节炎(OA)在美国影响着4000万人， 是65岁以上老年人残疾的主要原因。 目前，还没有任何形式的内科或外科治疗可以 预防、延缓发病或影响这种疾病的进展。 最近的人类流行病学数据表明，发病率和 服用安慰剂的女性膝关节骨性关节炎进展较慢 雌激素替代疗法(ERT)。这样做的总体目标是 建议是从适当的动物身上获得额外的数据 自然发生的骨性关节炎模型和从体外研究到 确定ERT作为干预措施的可能性，以防止 绝经后妇女骨性关节炎的发生和/或进展。 /具体目标是确定：1)长期ERT是否 降低绝经后女性骨性关节炎的严重程度。具体的 目的是确定：1)长期ERT是否会降低 手术治疗绝经后膝关节骨性关节炎的严重程度 食蟹猴；2)长期ERT对更替的影响 和软骨下和骨骺/干骺端松质骨体积 手术治疗绝经后食蟹猴胫骨中的骨 3)雌激素对猕猴关节软骨的影响 基质的合成和体外降解。目标1和目标2将是 通过对膝关节进行详细的形态检查 完成试验(30个月)的尸检收集的关节 持续时间)，旨在确定雌激素、孕激素、 和他莫昔芬对冠状动脉粥样硬化程度的影响 外科绝经期(双侧卵巢切除)食蟹猴 猴子。除了形态分级方案和详细的 关节软骨与骨、组织的组织形态计量学分析 切片将被免疫染色以检测OA的特定生物标记物 评估关节最早可能的形态变化 软骨对激素治疗的反应。对于目标3，细胞培养 从正常关节软骨中分离出软骨细胞 成年雌性食蟹猴将被进行检查 雌激素对基质合成和蛋白合成的潜在调节作用 退化。雌激素的作用将与雌激素的作用相比较。 黄体酮和他莫昔芬。这些拟议的研究提供了一个独特的 有机会获得可以支持和提供的信息 ERT对老年人进行全面介入研究的机制数据 人类骨性关节炎的治疗。

Osteoarthritis (OA) affects 40 million people in the United States and is the leading cause of disability among persons older than 65 years. Currently, there is no form of medical or surgical therapy that can prevent, delay the onset, or affect the progression of this disease. Recent human epidemiologic data suggest that the incidence and progression of OA of the knee is lower in women who have taken estrogen replacement therapy (ERT). The overall objective of this proposal is to obtain additional data, from an appropriate animal model of naturally occurring OA and from in vitro studies, to determine the potential for ERT as an intervention to prevent the development and/or progression of OA in postmenopausal women. /the specific aims are to determine: 1) whether long-term ERT decreases the severity of OA in postmenopausal women. The specific aims are to determine: 1) whether long-term ERT decreases the severity of OA of the knee joints in surgically postmenopausal cynomolgus monkeys; 2) the effects of long-term ERT on the turnover and volume of the subchondral and epiphyseal/metaphyseal cancellous bone in the promisal tibia of surgically postmenopausal cynomolgus monkeys; and 3) the effects of estrogen on monkey articular caritlage matrix synthesis and degradation in vitro. Aims 1 and 2 will be accomplished through detailed morphologic examinations of knee joints collected at necropsy from a completed trial (30 months duration) designed to determine the effects of estrogens, progestogens, and tamoxifen on the extent of coronary artery atherosclerosis in surgically menopausal (bilaterally of ovariectomized) cynomolgus monkeys. In addition to morphological grading schemes and detailed histomorphometric analysis of articular cartilage and bone, tissue sections will be immunostained for specific biological markers of OA to evaluate the earliest possible morphological changes in articular cartilage in response to hormonal treatments. For aim 3, cell culture of chondrocytes isolated from normal articular cartilage obtained from adult female cynomolgus monkeys will be performed to examine the potential modulatory effects of estrogen on matrix synthesis and degradation. The effects of estrogen will be compared to those of progesterone and tamoxifen. These proposed studies provide a unique opportunity to obtain information which could support and provide mechanistic data for a full interventional study of ERT for the treatment of OA in humans.