title: 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.
abstract: 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 (TRβ(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. We performed 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 β-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 TRβ(PV) that stabilizes β-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions between T(3) and Wnt signaling pathways in the regulation of skeletal development and bone formation.
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892; Molecular Endocrinology Group, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: O'Shea
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Molecular Endocrinology Group, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: John G
authors.initials: JG
authors.lastname: Logan
authors.affiliation: Molecular Genetics Section, Genetics Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.affiliation: Molecular Genetics Section, Genetics Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.affiliation: Molecular Genetics Section, Genetics Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Gene Regulation Section, Laboratory of Molecular Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892. Electronic address: chengs@mail.nih.gov.
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Molecular Endocrinology Group, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. Electronic address: graham.williams@imperial.ac.uk.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Williams
mesh_terms: D000818:Animals; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D010902:Pituitary Gland / Q000378:metabolism*; D055550:Protein Stability; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D037042:Thyroid Hormone Receptors beta; D051176:beta Catenin; D014284:Triiodothyronine