Endocrine Abstracts

Thyroid hormone (T3) is essential for skeletal development and maintenance of bone mineralisation. T3 actions are mediated by two receptors, TRalpha and TRbeta. Mutations in TRbeta cause autosomal dominant resistance to thyroid hormone (RTH) due to dominant negative activity of the mutant receptor. Short stature and abnormal skeletal development are prominent features of RTH, whereas TRalpha mutations have not been described and are postulated to result in no phenotype or to be lethal. To investigate T3 action during bone maturation, we examined skeletal development in mice harbouring a PV mutation targeted to either TRbeta or TRalpha1 by homologous recombination. The PV mutation was derived from a patient with RTH; TRbetaPV mice display severe RTH and recapitulate the human condition. TRalpha1PV mice, in contrast, exhibit mild thyroid failure with normal circulating hormone concentrations. TRbetaPV/PV homozygous mice were short, a phenotype that resulted from accelerated growth in utero followed by post-natal growth-retardation and premature growth plate quiescence. There was advanced ossification, increased bone mineralisation and craniosynostosis. In situ hybridisation studies revealed increased expression of the T3-target gene fibroblast growth factor receptor-1 in TRbetaPV/PV chondrocytes and osteoblasts. TRbetaPV/+ heterozygous mice displayed an intermediate phenotype with advanced bone formation but normal growth. In contrast, TRalpha1PV/PV mice died shortly after birth, whilst heterozygous TRalpha1PV/+ mice were dwarfs and exhibited severe growth retardation, reduced cortical bone formation and markedly delayed endochondral ossification. Thus, TRbetaPV mice display skeletal thyrotoxicosis and the severity of the phenotype correlates with the degree of RTH indicating that, in contrast to the pituitary, bone displays increased sensitivity to elevated T3 concentrations. In contrast, TRalpha1PV/+ mice exhibit a hypothyroid phenotype in bone and the PV mutation in TRalpha1 results in reduced skeletal sensitivity to T3. These data demonstrate that TRalpha is the major functional TR in bone in vivo.