Endocrine Abstracts

Childhood hypothyroidism results in severely delayed skeletal development whereas adult thyrotoxicosis is associated with a 3–4 fold increase in osteoporotic fracture. To investigate molecular mechanisms underlying these abnormalities we characterized the skeletal phenotypes of mice harboring dominant negative mutations (TRα1PV/+, TRα1R384C/+, TRβPV/PV) or deletions (TRα0/0, TRβ−/−) of the genes encoding TRα and TRβ. Endochondral ossification, linear growth and bone mineralization were retarded in TRα0/0 mice and more severely delayed in TRα1 dominant-negative mutants. In contrast, these parameters were all advanced in TRβ knockout and PV-mutant mice. In adults, 3D bone micro-architecture and micro-mineralization densities were analyzed by quantitative backscattered electron scanning electron microscopy. TRα mice displayed increased cortical bone width, and an 8–9 fold increase in trabecular bone volume with increased thickness of individual trabeculae and greater micro-architectural complexity. In contrast, analysis of all these parameters including quantitation of bone micro-mineralization density revealed TRβ mutants were markedly osteoporotic. Studies of T3-target gene expression revealed phenotypes of skeletal hypothyroidism in TRα mutant mice but skeletal thyrotoxicosis in TRβ mutants. We further demonstrated that TRα is expressed at 15-fold higher levels in bone than TRβ, whereas TRβ is predominantly expressed in hypothalamus and pituitary and controls negative feedback regulation of TRH and TSH. Accordingly, TRα mutant mice were euthyroid whereas TRβPV/PV and TRβ−/− displayed pituitary resistance to thyroid hormone with elevated circulating thyroid hormone levels. This analysis of a series of TR mutant mice with differing genetic backgrounds unequivocally demonstrates that TRα is the predominant TR isoform in bone, and shows that skeletal responses to disrupted TRβ signaling result from effects of the mutation on systemic thyroid status.