Endocrine Abstracts

T3-receptor alpha (TRa) is the predominant TR isoform in bone. To investigate its function, we analysed mice harbouring a dominant negative R384C mutation in TRa1 (TRa1^m/+). The homozygous TRa1^m/m mutation is lethal whereas heterozygotes are euthyroid displaying only transient postnatal hypothyroidism. Critically, dominant negative activity of the mutation is overcome by a 10-fold increase in T3, which is achieved by crossing TRa1^m/+ mutants with TRb^−/− mice. Thus, TRa1^m/+b^−/− mice represent a unique model to study reversibility of the R384C mutation. TRa1^+/+b^+/− (euthyroid), TRa1^m/+b^+/− (equivalent to TRa1^m/+) and TRa1^m/+b^−/− (10-fold increase in T3) mice were analysed between embryonic day 17.5 and 16 weeks of age. Histology revealed delayed endochondral ossification in TRa1^m/+b^+/− mice with a maximum 15% reduction in bone length at 2 weeks (P<0.05). TRa1^m/+b^−/− mice displayed only a minor delay until 4 weeks of age. Intramembranous ossification was also delayed in TRa1^m/+b^+/− and TRa1^m/+b^−/− mice with a >2-fold increase in cranial fontanelle area at birth (P<0.001). Bone micro-architecture and micro-mineralisation densities, analysed by quantitative backscattered electron scanning electron microscopy, revealed a 2.7-fold increase in trabecular bone volume (BVF) in adult TRa1^m/+b^+/− mice (P<0.01) and increased trabecular complexity, thickness and micro-mineralisation density (P<0.001). Extension of trabecular bone into the diaphysis increased from 10% of total bone length in TRa1^+/+b^+/− and TRa1^m/+b^−/− mice to 33% in TRa1^m/+b^+/− mice (P<0.001). To compensate for the period of transient hypothyroidism during growth, some TRa1^m/+b^+/− mice were treated with T3 between days 10 and 35. T3-treated adult TRa1^m/+b^+/− mice had reduced trabecular thickness, complexity and micro-mineralisation density but TRa1^+/+b^+/− mice were unaffected (P<0.001), indicating that a short period of T3 treatment during growth profoundly influences adult bone structure. Crossing TRa1^m/+ mice with TRb^−/− mice further rescued the adult phenotype. These data demonstrate that TRa plays a critical role in establishing adult bone structure and mineralisation.