Role of thyroid hormones in skeletal development and bone maintenance
JH Duncan Bassett, Graham R Williams
AbstractThe skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance.
Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones.
Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art.
Summary and future directionsThe skeleton is exquisitely sensitive to thyroid hormones, which have profound effects on bone development, linear growth, and adult bone maintenance.
Thyroid hormone deficiency in children results in cessation of growth and bone maturation, whereas thyrotoxicosis accelerates these processes. In adults, thyrotoxicosis is an important and established cause of secondary osteoporosis, and an increased risk of fracture has now been demonstrated in subclinical hyperthyroidism. Furthermore, even thyroid status at the upper end of the normal euthyroid reference range is associated with an increased risk of fracture in postmenopausal women.
An extensive series of studies in genetically modified mice has shown that T3 exerts anabolic actions on the developing skeleton and has catabolic effects in adulthood, and these actions are mediated predominantly by TRα1. The importance of the local regulation of T3 availability in bone has been demonstrated in studies that identified a critical role for DIO2 in osteoblasts to optimize bone mineralization and strength.
The translational importance and clinical relevance of such studies is highlighted by the characterization of mice harboring deletions or dominant-negative mutations of Thra, which accurately predicted the abnormalities seen in patients recently identified with RTHα. Moreover, mice with dominant-negative mutations of Thra also represent an important disease model in which to investigate novel therapeutic approaches in these patients.
In addition to studies in genetically modified mice, analysis of patients with thyroid disease or inherited disorders of T3 action is consistent with a major physiological role for T3 in the regulation of skeletal development and adult bone maintenance. Analysis of Tshr−/− mice and studies of TSH administration in rodents have also suggested that TSH acts as a negative regulator of bone turnover. Nevertheless, the physiological role of TSH in the skeleton remains uncertain because its proposed actions are not wholly consistent with findings in human diseases and mouse models in which the physiological inverse relationship between thyroid hormones and TSH is dissociated.
Precise determination of the cellular and molecular mechanisms of T3 and TSH actions in the skeleton in vivo will require cell-specific conditional gene targeting approaches in individual bone cell lineages. Combined with genome-wide gene expression analysis, these approaches will determine key target genes and downstream signaling pathways and have the potential to identify new therapeutic targets for skeletal disease.
Recent studies have also identified DIO2 and DIO3 as disease susceptibility loci for OA, a major degenerative disease of increasing prevalence in the aging population. These data establish a new field of research and further highlight the fundamental importance of understanding the mechanisms of T3 action in cartilage and bone and its role in tissue maintenance, response to injury, and pathogenesis of degenerative disease.