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

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.

Osteoporosis is characterized by low bone mass and increased susceptibility to fracture. Oestrogen (E2) conserves bone mass whereas thyroid hormone (T3) stimulates bone resorption, suggesting their opposing interactions are important in the pathogenesis of bone loss. T3-action is mediated by two receptors (TR alpha and beta), which are expressed in distinct ratios in different tissues. TR beta is the major isoform in pituitary and controls negative feedback regulation of TSH. TR alpha is predominant in bone and is the main regulator of skeletal development and bone maintenance. Global inactivation of TR alpha causes skeletal hypothyroidism and delayed ossification, but preserves bone mass in adults. Global inactivation of TR beta accelerates growth and bone development, but causes osteoporosis in adults. The consequences of TR alpha-inactivation result from impaired T3-action in bone, whereas TR beta-inactivation affects the pituitary causing impaired negative feedback of TSH, which results in thyrotoxic levels of circulating thyroid hormones that act via TR alpha in bone to induce skeletal thyrotoxicosis. T3 also regulates activity of other pathways that influence bone mass, as well as exerting direct actions in bone. Thus, local T3-actions in bone and the systemic effects of altered thyroid status cannot be separated by global gene targeting. These studies aim to characterize skeletal T3-actions, and interactions with E2, using tissue-specific gene targeting strategies to address the hypotheses that (i) T3-dependent bone growth and mineralization is necessary to establish normal bone structure in adulthood, (ii) E2-deficiency exposes the skeleton to the pro-resorptive actions of T3 leading to accelerated bone loss, and (iii) T3-induced bone loss following E2 withdrawal is mediated by TR alpha. We will generate tissue-specific knockouts of TR alpha, beta or both receptors in chondrocytes and osteoblasts, and characterize their effects on the skeleton. To investigate interactions between E2 and T3, we will determine the effects of ovariectomy in osteoblast-specific TR-knockouts. To characterize the role of TR alpha in bone maintenance, effects of treatment with a TR alpha-selective antagonist will be determined. Phenotypes will be demonstrated by histology, in situ hybridization and immunohistochemistry during development and by quantitative back-scattered electron scanning electron microscopy analysis of 3D bone structure and micromineralization in adulthood. These studies will provide a new understanding of T3 action in bone and its role in the pathogenesis of accelerated bone loss, and a rationale for therapeutic targeting of TR alpha in osteoporosis prevention and treatment.