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Endocrine Abstracts (2006) 11 OC54

ECE2006 Oral Communications Calcium and bone OC49 Novartis Oncology Young Investigator Award (8 abstracts)

Adult mice harbouring a dominant negative R384C mutation of TRalpha1 have a marked increase in trabecular bone and micro-mineralisation density

JHD Bassett 1 , K Nordstrom 2 , B Vennstrom 2 , PGT Howell 3 , A Boyde 4 & GR Williams 1

1Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom; 2Department of Molecular Biology, Karolinska Institute, Stockholm, Sweden; 3Eastman Dental Institute, University College London, London, United Kingdom; 4Centre for Oral Growth and Development, Queen Mary, University of London, London, United Kingdom.

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 (TRa1m/+). The homozygous TRa1m/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 TRa1m/+ mutants with TRb−/− mice. Thus, TRa1m/+b−/− mice represent a unique model to study reversibility of the R384C mutation. TRa1+/+b+/− (euthyroid), TRa1m/+b+/− (equivalent to TRa1m/+) and TRa1m/+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 TRa1m/+b+/− mice with a maximum 15% reduction in bone length at 2 weeks (P<0.05). TRa1m/+b−/− mice displayed only a minor delay until 4 weeks of age. Intramembranous ossification was also delayed in TRa1m/+b+/− and TRa1m/+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 TRa1m/+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 TRa1m/+b−/− mice to 33% in TRa1m/+b+/− mice (P<0.001). To compensate for the period of transient hypothyroidism during growth, some TRa1m/+b+/− mice were treated with T3 between days 10 and 35. T3-treated adult TRa1m/+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 TRa1m/+ 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.

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
British Endocrine Societies 

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