Thyroid hormone receptors and the regulation of bone physiology

Abstract: The aim of the studies in this thesis was to investigate the role of thyroid hormone receptors in bone physiology. Thyroid hormone signals through its receptors, the TRs, and has profound effects on bone development and metabolism, as demonstrated in hypo- and hyperthyroidism. The thyroid hormone receptor isoforms TRa1, TRa2 and TRb1 are expressed by osteoblasts, osteoclasts and chondrocytes in bone tissue. Three different mouse models have been studied in order to understand the functions of the TRs. TRa1-/-b-/- mice lack all thyroid hormone-binding capacity and have a severe skeletal phenotype characterised by pre- and postnatal growth retardation, defective mineralisation and a reduction in the GH/IGF-I axis. When these mice receive GH-substitution, serum IGF-I levels become normalised and the mice exhibit catch-up growth. GH-substitution induces significant increases in dimensional parameters of the long bones in TRa1-/-b-/- mice, but in contrast, the defective mineralisation is not affected by GH. Furthermore, TRa1-/-b-/- mice have reduced trabecular bone mineral density (BMD) associated with an increased amount of fat in the bone marrow. The increased bone marrow fat reflects an increased number of adipocytes and increased mRNA levels of genes specific for mature adipocytes. Thus, TRa1-/-b-/- mice have a severe skeletal phenotype. The GH-deficiency is important for the origin of the growth retardation in these mice and, in addition, the increased bone marrow fat and reduced trabecular BMD might reflect an imbalance in the differentiation of adipocytes and osteoblasts from the common progenitor cell.TRa2-/- mice lack the non ligand-binding receptor isoform a2 but, as an inevitable consequence, they overexpress TRa1. TRa2-/- mice exhibit normal longitudinal growth and bone maturation, but have a reduction in BMD and the amount of cortical bone, resembling osteopenia. Thus, deficiency in TRa2/overexpression of TRa1 is compatible with normal postnatal growth and bone maturation but is of importance for adult bone metabolism. TRa1+/m mice have a mutation in the TRa1 gene originally discovered in TRb in a family with resistance to thyroid hormone (RTH). The mutated receptor has dominant negative properties and causes a juvenile phenotype with growth retardation and delayed bone maturation, which is overcome in adult mice. The compensatory mechanisms behind this recovery are not known but they might include normalised TH and GH levels in adulthood.Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP) are important for the process of endochondral bone formation, which mediates longitudinal bone growth, and their expression is regulated by thyroid hormone in rodents. Ihh and PTHrP were also detected in the human growth plate, and the level of expression was down-regulated with advancing puberty. Factors that regulate pubertal growth and the eventual fusion of the growth plate might therefore be involved in the regulation of Ihh and PTHrP.In conclusion, TRs are crucial to bone development and physiology. Furthermore, ligand deficiency is associated with more severe consequences for bone physiology than receptor deficiency. An increased understanding of the effects of thyroid hormone signalling in the skeleton may result in new treatment strategies for children with growth disturbances and adults with osteoporosis.