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Thyroid status during skeletal development determines adult bone structure and mineralization

Bassett, JHD; Nordstrom, K; Boyde, A; Howell, PGT; Kelly, S; Vennstrom, B; Williams, GR; (2007) Thyroid status during skeletal development determines adult bone structure and mineralization. MOL ENDOCRINOL , 21 (8) 1893 - 1904. 10.1210/me.2007-0157.

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Abstract

Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T-3) during development manifest in adult bone, we characterized TR alpha 1+/m beta+/- mice, which express a mutant T-3 receptor (TR) alpha 1 with dominant- negative properties due to reduced ligand- binding affinity. Remarkably, adult TR alpha 1+/m beta+/- mice had osteosclerosis mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T-3 treatment of juveniles and fully reversed in compound TR alpha 1+/m beta+/- mutant mice due to 10- fold elevated hormone levels that allow the mutant TR alpha 1 to bind T-3. By contrast, deletion of TR beta in TR alpha 1+/+beta-/- mice, which causes a 3- fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T-3-target gene analysis revealed skeletal hypothyroidism in TR alpha+1m/+beta+/- mice, thyrotoxicosis in TR alpha 1+/+/beta-/- mice, and euthyroidism in TR alpha 1+/beta-/- double mutants. Thus, TR alpha 1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization.

Type: Article
Title: Thyroid status during skeletal development determines adult bone structure and mineralization
DOI: 10.1210/me.2007-0157
Keywords: HORMONE RECEPTOR-ALPHA, POSTNATAL-DEVELOPMENT, RESORPTION, GROWTH, MICE, FRACTURE, HYPERTHYROIDISM, HYPOTHYROIDISM, PHENOTYPE, RISK
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute
URI: http://discovery.ucl.ac.uk/id/eprint/9961
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