Thyroid hormone (T3) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance but the signaling pathways mediating these effects are poorly understood. ThrbPV/PV mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant-negative mutant T3-receptor (TRβPV) that cannot bind T3 and interferes with the actions of wild-type TR.ThrbPV/PV mice have accelerated skeletal development due to unknown mechanisms. We performed microarray studies in primary osteoblasts from wild-type mice and ThrbPV/PV mice. Activation of the canonical Wnt signaling in ThrbPV/PV mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during post-natal growth.By contrast, T3 treatment inhibited Wnt signaling in osteoblastic cells, suggesting T3 inhibits the Wnt pathway by facilitating proteasomal degradation of β-catenin and preventing its accumulation in the nucleus.Activation of the Wnt pathway in ThrbPV/PV mice, however, results from a gain-of-function for TRβPV that stabilizes β-catenin despite the presence of increased thyroid hormone levels.These studies demonstrate novel interactions between T3 and Wnt signaling pathways in the regulation of skeletal development and bone formation.
 


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