Role of skeletal thyroid hormone receptors in the regulation of bone mass

甲状腺激素(T3)对骨骼的发育和生长过程中骨骼的矿化是必不可少的。在成年人中，过量的T3会导致骨质流失，是骨质疏松症和骨折的危险因素。骨质疏松症的特征是骨密度降低，骨折易感性增加。这是一种常见的疾病，50岁以上的女性中有一半患有此病，男性中有五分之一患有此病，每年给NHS造成的损失超过17亿英镑。加速骨质流失和骨质疏松的主要原因是雌激素缺乏，但目前尚不清楚雌激素缺乏实际上是如何导致骨丢失的。雌激素通常保留骨骼，而T3促进骨吸收。我们认为这些相反的行为参与了骨质疏松症的发生发展。具体地说，我们假设，在绝经期，由于雌激素不能拮抗T3的骨吸收作用，所以会发生加速的骨丢失。对对甲状腺激素作用有抵抗力的人类和甲状腺激素受体缺失的动物模型的研究表明，甲状腺激素受体α对甲状腺激素调节骨骼发育和骨骼维持至关重要。T3也作用于骨骼以外的其他组织，目前对T3对骨骼影响的了解受到以下事实的限制：临床研究和现有的动物模型无法将骨骼中特定的T3作用与更普遍的影响骨骼新陈代谢的作用分开。为了解决这个问题，我们将建立小鼠模型，在这些模型中，甲状腺激素受体只从骨骼细胞中移除。这些模型将使我们能够表征T3的骨骼特异性行为，并研究T3和雌激素如何在正常的骨维持调节中相互作用。我们还将确定T3受体α的选择性拮抗剂是否能保护骨量，防止雌激素缺乏引起的骨丢失。这些研究将帮助我们了解是什么决定了加速的骨丢失，并可能导致治疗骨质疏松症的新药的开发。这些研究结果的细节将在帝国理工学院和哈默史密斯医院出版的研发通讯和网站上公布。

Thyroid hormone (T3) is essential for development of the skeleton and mineralization of bone during growth. In adults, an excess of T3 causes bone loss and is a risk factor for osteoporosis and fracture. Osteoporosis is characterized by reduced bone density and increased susceptibility to fracture. It is a common disease that affects half of the women and one in five men over 50, and costs the NHS over #1.7 billion per annum. The major cause of accelerated bone loss and osteoporosis is oestrogen deficiency, but it is not clear how a lack of oestrogen actually induces bone loss. Oestrogen normally preserves bone whereas T3 promotes bone resorption. We propose that these opposing actions are involved in the development of osteoporosis. Specifically, we hypothesise that, at the menopause, accelerated bone loss occurs because the bone resorbing actions of T3 are not antagonized by oestrogen. Studies of humans with resistance to the actions of thyroid hormones and animal models, in which thyroid hormone receptors have been deleted, suggest that the thyroid hormone receptor alpha is primarily important for the regulation of skeletal development and bone maintenance by thyroid hormone. T3 also acts in tissues other than bone, and the current understanding of T3 effects on the skeleton is limited by the fact that clinical studies and available animal models cannot separate specific T3-actions in bone from more general effects that also influence skeletal metabolism. To resolve this problem we will generate mouse models in which thyroid hormone receptors have been removed only from bone cells. These models will allow us to characterize the bone-specific actions of T3 and investigate how T3 and oestrogen interact in the normal regulation of bone maintenance. We will also determine whether selective antagonists of T3 receptor alpha preserve bone mass and prevent bone loss resulting from oestrogen deficiency. These studies will help us to understand what determines accelerated bone loss and may lead to the development of new drugs for the treatment of osteoporosis. Details of results from these studies will be publicised in Research and Development newsletters and websites published by Imperial College and Hammersmith Hospital.