Thyroid hormones are essential for skeletal development and bone maintenance. Childhood hypothyroidism causes growth arrest with delayed bone maturation, whereas thyrotoxicosis accelerates growth and advances bone age. In adults, thyrotoxicosis causes osteoporosis and increased susceptibility to fracture. To investigate mechanisms of T3 action in bone, we analyzed T3 receptor (TR) mutant mice. TRα-null (TRα0/0) mice are euthyroid but display delayed ossification with growth retardation and reduced mineralized bone deposition. TRβ-null (TRβ−/−) mice have resistance to thyroid hormone (RTH) with increased circulating thyroid hormones. They display advanced ossification with accelerated growth plate narrowing and increased mineralized bone. These phenotypes were verified by examining TRα1PV and TRβPV mutant mice, which harbour a frame-shift mutation (PV) in the TR coding region. PV-mutant TRs cannot bind T3 or activate TR-target genes and they act as dominant-negative inhibitors of wild-type TR function. TRα1PV mice are severely growth retarded with delayed ossification despite normal T4 and T3 levels, whereas TRβPV mice have severe RTH with 12-15 fold elevated hormone concentrations and exhibit advanced ossification with increased mineralized bone deposition. Thus, TRα0/0 and TRα1PV mice exhibit a hypothyroid bone phenotype, whereas TRβ−/− and TRβPV mice display skeletal thyrotoxicosis. The skeletal effects of TRα mutation result from disruption of TRα action in bone, whereas effects of TRβ mutation result from thyrotoxicosis (induced by disruption of TRβ action in the pituitary) and are mediated by over-stimulation of TRα in bone. Preliminary analysis of bone structure in adult mice has revealed TRα mutants have high bone mass with increased trabecular number and thickness. In contrast, TRβ mutants display osteoporosis with reduced trabecular number and thickness. These studies indicate that TRα is essential for skeletal development during growth and for preservation of bone in adulthood.
07 - 09 Nov 2005
Society for Endocrinology