Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2011) 25 PL6

Imperial College London, London, UK.

Hypothyroidism delays bone formation, whilst thyrotoxicosis accelerates skeletal development but is a risk factor for osteoporosis. We characterized mice with mutation or deletion of T3 receptors, TRα and TRβ, in several genetic backgrounds. Delayed ossification and growth retardation were observed in TRα mutants, whereas TRβ mutants had advanced bone age. Adult TRα mutants had high bone mass, whereas TRβ mutants were osteoporotic. Target gene expression was reduced in growth plate chondrocytes and osteoblasts in TRα mutants indicating tissue hypothyroidism, whereas increased expression in TRβ mutants demonstrated tissue hyperthyroidism. TRα was expressed at much higher levels than TRβ in bone at all ages, whereas TRβ controls feedback regulation of the hypothalamic–pituitary–thyroid axis. Consequently, TRα mutant mice were euthyroid but TRβ mutants had elevated thyroid hormone concentrations and pituitary resistance to thyroid hormone. Thus, TRα mediates T3 action in bone whereas the consequences of TRβ disruption are due to effects on systemic thyroid status. Conversion of T4 to active T3 is mediated by the type 2 deiodinase (D2) whilst the type 3 enzyme (D3) inactivates T4 and T3. The relative expression of D2 and D3 thus determines intra-cellular availability of T3 and regulates thyroid hormone responsiveness in target cells. We showed that D2 activity in bone is restricted to osteoblasts and found that D2 knockout mice have normal skeletal development but increased bone mineralization and brittle bones in adulthood. The phenotype resulted from a discrete defect of osteoblast function, demonstrating an essential role for D2 to optimize bone mineralization and strength. Recently, we over-expressed D3 in chondrocytes by cre-lox mediated gene targeting to generate mice with cartilage-specific thyroid hormone deficiency. These studies have identified a major new role for thyroid hormones in chondrocytes that is required to establish the normal structure of joints and adult bone.

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