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

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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.