Endocrine Abstracts (2006) 11 P10

Thyroid hormone receptor alpha has a critical negative role in maintenance of the adult skeleton

JHD Bassett1, PJ O’Shea1, A Boyde2, PGT Howell3, J Samarut4, O Chassande5 & GR Williams1


1Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom; 2Centre for Oral Growth and Development, Queen Mary, University of London, London, United Kingdom; 3Eastman Dental Institute, University College London, London, United Kingdom; 4Laboratoire de Biologie Moléculaire et Cellulaire de l’Ecole Normale Supérieure de Lyon, Lyon, France; 5Biomatériaux et Réparation Tissulaire INSERM U 443, Université de Bordeaux 2, Bordeaux, France.


In developmental studies of mice lacking T3-receptor alpha (TRa0/0) and beta (TRb−/−) we demonstrated delayed endochondral ossification, reduced mineralisation and short stature in TRa0/0 mice, despite euthyroidism. In contrast, TRb−/− mice, which display thyroid hormone resistance with elevated T4 and T3 levels, have advanced ossification, increased mineralisation and accelerated growth. T3-target gene studies indicate that TRa0/0 mice have skeletal hypothyroidism, whereas TRb−/− bone is thyrotoxic. To investigate whether these abnormalities influence the adult skeleton, we studied euthyroid and T4-treated 22 week-old TRa0/0 and TRb−/− mice. There was no difference in bone length between WT, TRa0/0 and TRa0/0(+T4) mice, whereas TRb−/− and TRb−/−(+T4) bones were shorter by 5% and 4%, respectively (P<0.01). Histology revealed an 11% increase in cortical thickness in TRa0/0 mice but 16% reduction in TRb−/−. T4 treatment reduced cortical thickness by 27% in TRa0/0 mice (P<0.05) and 29% in TRb−/− (P<0.001). Bone micro-architecture and micro-mineralisation densities, analysed by quantitative backscattered electron scanning electron microscopy, demonstrated a 2.8-fold increase in trabecular bone volume (BVF) in TRa0/0 mice (P<0.01) and increased trabecular thickness and complexity. Extension of trabecular bone into the diaphysis increased from 10% of total bone length in WT to 29% in TRa0/0 (P<0.01). T4-treatment reduced trabecular thickness and complexity and BVF by 42% (P<0.05), and trabecular bone extent by 20% (P<0.05) in TRa0/0 mice. In contrast, all trabecular bone parameters were reduced in TRb−/− mice and unaffected by T4-treatment. Quantitative micro-mineralisation measurements were similar in TRa0/0 and WT animals, whereas TRb−/− mice had reduced trabecular and cortical mineral concentration (P<0.001). Thus, adult TRa0/0 mice have increased bone of normal mineralisation density, whilst TRb−/− mice are osteoporotic. These data demonstrate that TRalpha plays critical roles in skeletal development, and in the establishment and maintenance of adult bone structure. TRb can partially compensate for TRa in TRa0/0 mice.

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