Advanced Bone Formation in Mice with a Dominant-negative Mutation in the Thyroid Hormone Receptor β Gene due to Activation of Wnt/β-Catenin Protein Signaling

Thyroid hormone (T-3) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance, but the signaling pathways mediating these effects are poorly understood. Thrb(PV/PV) mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant- negative mutant T-3 receptor (TR beta(PV)) that cannot bind T-3 and interferes with the actions of wild-type TR. Thrb(PV/PV) mice have accelerated skeletal development due to unknown mechanisms. Weperformed microarray studies in primary osteoblasts from wild-type mice and Thrb(PV/PV) mice. Activation of the canonical Wnt signaling in Thrb(PV/PV) mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during postnatal growth. By contrast, T-3 treatment inhibited Wnt signaling in osteoblastic cells, suggesting that T-3 inhibits the Wnt pathway by facilitating proteasomal degradation of beta-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in Thrb(PV/PV) mice, however, results from a gain of function for TR beta(PV) that stabilizes beta-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions betweenT(3) and Wnt signaling pathways in the regulation of skeletal development and bone formation.