Thyroid status during skeletal development determines adult bone structure and mineralization

Abstract

Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T3) during development manifest in adult bone, we characterized TRα1+/mβ-/- mice, which express a mutant T3 receptor (TR) α1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TRα1 +/mβ-/- mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T3 treatment of juveniles and fully reversed in compound TRα1+/mβ-/- mutant mice due to 10-fold elevated hormone levels that allow the mutant TRα1 to bind T3. By contrast, deletion of TRβ in TRα1 +/+β-/- mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T3-target gene analysis revealed skeletal hypothyroidism in TRα1m/+β+/- mice, thyrotoxicosis in TRα1+/+β-/- mice, and euthyroidism in TRα1+/β-/- double mutants. Thus, TRα1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization. Copyright © 2007 by The Endocrine Society.