Endocrine Abstracts (2002) 3 OC20

Advanced bone formation in mice with resistance to thyroid hormone due to a targeted mutation in the thyroid hormone receptor beta gene

PJ O'Shea1, CB Harvey1, H Suzuki2, M Kaneshige2, K Kaneshige2, S-y Cheng2 & GR Williams1

1Imperial College of Science Technology and Medicine Molecular Endocrinology Group, Hammersmith Hospital, London, UK; 2Laboratory of Molecular Biology NCI NIH, Bethesda MD, USA.

Thyroid hormone (T3) receptor beta (TRbeta) mutations cause resistance to thyroid hormones (RTH), characterised by decreased tissue sensitivity to T3. The TRbetaPV mutation (C-insertion at codon 448 leads to a frameshift of the carboxy-terminal 14 amino acids) was derived from a patient with severe RTH and generates a receptor lacking T3-binding and transactivation activities. Heterozygous mutant mice have a mildly impaired pituitary-thyroid axis; severe RTH and limb shortening occurs in homozygotes. We examined the skeletal phenotype of TRbetaPV mice to determine the basis for short stature. Whole skeletons were stained with alizarin red/alcian blue; mineralised and decalcified bone sections with von Kossa and van Gieson/alcian blue. TRbetaPV homozygous mutants showed 10% growth retardation at 3 weeks, particularly in the upper limbs, with reduced weight gain between 2 and 10 weeks compared to heterozygous and wild-type littermates. E17.5 and neonatal mutants showed no differences to wild-type at all skeletal sites other than the skull, which was smaller with increased ossification in neonatal homozygous mutants. Increased trabecular bone formation and mineralisation was evident in 2-week heterozygous and homozygous mutants. There was increased alizarin red staining of bone, and growth plate narrowing with reduced alcian blue staining, in upper and lower limb mounts from 3-week homozygous mutants. Histology revealed narrowing of the hypertrophic zone and advanced endochondral ossification in growth plates from 3-week mutant mice; changes being more severe in homozygous mutants. By 4 weeks there was focal growth plate calcification in homozygous mutants but not in wild-type or heterozygous littermates. Surprisingly, therefore, a thyrotoxic phenotype of advanced ossification with premature growth plate narrowing accounts for the short stature in TRbetaPV mutant mice. In contrast to the pituitary, the skeleton displays increased sensitivity to elevated T3 concentrations in RTH, suggesting that TRalpha is the dominant TR in bone.

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