SFEBES2008 Oral Communications Thyroid (8 abstracts)
Increased skeletal mineralisation in mice lacking type 2 iodothyronine deiodinase
JH Duncan Bassett 1 , Alan Boyde 2 , Peter GT Howell 3 , Thomas M Galliford 1 , Marta Archanco 1 , Donald L St Germain 4 , Valerie A Galton 4 & Graham R Williams 1
1Molecular Endocrinology Group, Imperial College London, London, UK; 2Centre for Oral Growth and Development, Queen Mary, University of London, London, UK; 3Eastman Dental Institute, University College London, London, UK; 4Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
The prohormone T4 represents the majority of circulating thyroid hormones, whereas 80% of the active hormone T3 is derived from T4 by the actions of the type 1 and type 2 deiodinase enzymes (D1 and D2). Local generation of T3 by D2 regulates ligand supply to the nuclear T3-receptor in pituitary, brown adipose tissue and brain, and this enzyme is also expressed in bone. Hypothyroidism in children causes delayed bone age and growth retardation, whereas thyrotoxicosis in adults causes osteoporosis. To determine whether local generation of T3 is essential in bone, we examined two knockout mouse models, one lacking D2 activity (D2KO) and the other lacking both D1 and D2 activities (D1/D2KO). Both mutants have mildly elevated serum T4 and TSH but normal T3 levels. In juveniles, endochondral and intramembranous ossification, cortical bone thickness and linear growth were similar in D2KO and wild-type mice. In adults, bone microarchitecture and mineralisation were determined by back-scattered electron scanning electron microscopy. D2KO mice exhibited 20% reduction in trabecular bone volume (P<0.01) and greatly increased trabecular and cortical bone mineralisation density (P<0.001). These abnormalities were accompanied by 36% reduction in bone mineral apposition rate (P<0.05) and 23% reduction in the mineralising to total bone surface ratio (MS/BS) determined by confocal scanning light microscopy of dynamic bone formation following dual calcein labelling. Osteoclast resorption surfaces were similar in D2KO and wild-type mice. The phenotype of D2KO mice was not modified by additional deletion of D1 in D1/D2KO mice, indicating D1 has no physiological role in bone. By contrast, the absence of a phenotype during growth but marked abnormality of bone formation and mineralisation in adult D2KO mice demonstrates that local T3 production is essential for physiological regulation of bone turnover and mineralisation by thyroid hormones, but is not limiting during skeletal development.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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