Thyroid status during skeletal development determines adult bone structure and mineralization

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.