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Bone Abstracts (2014) 3 W4.3 | DOI: 10.1530/boneabs.3.W4.3

Endocrine regulation of bone

Thyroid hormones and bone

Graham Williams

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London, UK.


Hypothyroidism delays bone development and linear growth, whereas thyrotoxicosis accelerates skeletal development and is an important risk factor for osteoporosis in adulthood. Even sub-clinical thyrotoxicosis is associated with fracture, and treatment with thyroxine at doses that suppress TSH results in increased bone turnover and low BMD in postmenopausal women.

To investigate the mechanism of T3 action in the skeleton, we characterized mice with mutation or deletion of T3 receptor (TR) α and TRβ in several genetic backgrounds. Delayed ossification was accompanied by growth retardation in TRα mutant mice, whereas juvenile TRβ mutant mice had advanced ossification but persistent short stature due to early growth plate quiescence. Adult TRα mutants had skeletal dysplasia and osteosclerosis, whereas TRβ mutants were osteoporotic. T3 target gene expression was reduced in osteoblasts and growth plate chondrocytes in TRα mutant mice but increased in TRβ mutants, indicating impaired skeletal T3 action in TRα mutants but enhanced signalling in TRβ mutants. TRα was expressed at 15-fold higher levels than TRβ in bone, whereas TRβ predominates in hypothalamus and pituitary, where it controls feedback regulation of TSH secretion. Accordingly, TRα mutant mice were euthyroid, whereas TRβ mutants had elevated circulating thyroid hormone concentrations with pituitary resistance to thyroid hormone. These data demonstrate that TRα is the major functional TR in bone, whereas skeletal responses to disruption of TRβ result from effects on the hypothalamic–pituitary–thyroid axis resulting in elevated circulating thyroid hormone concentrations.

Recently, four individuals with dominant-negative mutations of TRα have been identified. These children exhibit skeletal dysplasia characterised by delayed ossification, growth retardation, epiphyseal dysgenesis, patent fontanelles, and macrocephaly, and thus demonstrate the critical role for TRα in bone formation and maturation in humans.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

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