Estrogen regulation of osteoclastogenesis in older men

本R03提案是对研究目标#17的回应，标题为肌肉骨骼衰老的基本机制。男性骨质疏松症和髋部骨折，主要是老年男性的疾病，直到最近才得到很好的研究。虽然有许多因素会导致骨质疏松症并决定骨折风险，但已知性腺类固醇随着年龄的增长而减少会影响男性和女性的骨代谢。最近的证据表明雌激素（E2）对男性骨骼健康的重要性。E2发挥多种重要的生理作用，这些作用是通过两种雌激素受体介导的， 成人骨，尽管它们相互作用的机制还不清楚。在前期工作中，我们发现小鼠卵巢切除后，骨髓细胞分化为破骨细胞的能力迅速增加，破骨细胞是介导骨吸收的细胞。这一发现表明，E2调节造血前体细胞分化成破骨细胞的能力，这一过程尚未得到充分的研究。这项建议的研究代表了基础和临床研究人员之间的合作，他们希望确定老年男性的人骨髓细胞是否以类似于我们在小鼠模型中证明的方式对E2产生反应。由于骨吸收率增加 似乎是已知的最早的雌激素撤退对人类骨骼的影响，一个更好的 对这一过程的理解可能会导致更有效的治疗男性和女性骨质疏松症的疗法。为了更好地理解E2在男性中的作用，一个独特的模型是用LHRH激动剂进行激素抑制治疗局部晚期前列腺癌的男性。这种疗法会导致性腺功能减退，在几周内睾酮（T）和E2水平都很低。由于E2疗法以前曾被用于实现药物去势，因此在这些男性中添加E2是可以接受的，并允许研究E2治疗的效果。 E2对骨骼的作用机制，而没有T的同时影响。随着对E2作用于男性骨代谢的机制的更好理解，应该可以更精确地分析这些相互作用，并在更好地理解这些相互作用的基础上开发更具体的干预措施。

This R03 proposal is in response to Research Objective #17, entitled Basic Underlying Mechanisms of Musculoskeletal Aging. Male osteoporosis and hip fractures, primarily diseases of older men, have been poorly studied until recently. While there are numerous factors that cause osteoporosis and determine fracture risk, decreases in gonadal steroids with aging are known to influence bone metabolism in both men and women. Recent evidence has demonstrated the importance of estrogen (E2) in male bone health. E2 exerts a variety of important physiological effects, which are mediated via two estrogen receptors found in adult bone, although the mechanisms by which they interact is not well understood. In preliminary work we have found that ovariectomy in mice is rapidly followed by an increase in the ability of bone marrow cells to differentiate into osteoclasts, the cells that mediate bone resorption. This finding suggests that E2 regulates the ability of hematopoietic precursor cells to differentiate into osteoclasts, a process that has not been adequately examined. The studies of this proposal represents a collaboration between basic and clinical researchers who wish to determine if human bone marrow cells from older men respond to E2 in a manner similar to that which we have demonstrated in our murine model. Since increased rates of bone resorption appear to be the earliest known effects of estrogen withdrawal on the human skeleton, a better understanding of this process may lead to more effective therapies for the treatment of osteoporosis in both men and women. A unique model in which to better understand the role of E2 in men is that of men undergoing hormonal suppression with LHRH agonists for locally advanced prostate cancer. This therapy leads to hypogonadism, with both low testosterone (T) and E2 levels within a few weeks. Since E2 therapy has been previously used to achieve medical castration, adding back E2 in these men is acceptable and allows the study of the mechanisms of E2 action on bone without the simultaneous influence of T. As the mechanisms of E2 action on male bone metabolism are better understood, it should be possible to analyze these interactions more precisely and develop more specific interventions based on a better understanding of these interactions.