title: 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 TRalpha1(+/m)beta(+/-) mice, which express a mutant T3 receptor (TR) alpha1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TRalpha1(+/m)beta(+/-) 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 TRalpha1(+/m)beta(-/-) mutant mice due to 10-fold elevated hormone levels that allow the mutant TRalpha1 to bind T3. By contrast, deletion of TRbeta in TRalpha1(+/+)beta(-/ -) 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 TRalpha1(m/+)beta(+/-) mice, thyrotoxicosis in TRalpha1(+/+)beta(-/-) mice, and euthyroidism in TRalpha1(+/)beta(-/-) double mutants. Thus, TRalpha1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization.
authors.affiliation: Molecular Endocrinology Group, MRC Clinical Sciences Center, Hammersmith Hospital, London W12 0NN, United Kingdom.
authors.forename: J H Duncan
authors.initials: JH
authors.lastname: Bassett
authors.forename: Kristina
authors.initials: K
authors.lastname: Nordström
authors.forename: Alan
authors.initials: A
authors.lastname: Boyde
authors.forename: Peter G T
authors.initials: PG
authors.lastname: Howell
authors.forename: Shane
authors.initials: S
authors.lastname: Kelly
authors.forename: Björn
authors.initials: B
authors.lastname: Vennström
authors.forename: Graham R
authors.initials: GR
authors.lastname: Williams
mesh_terms: D000818:Animals; D001846:Bone Development / Q000502:physiology*; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000166:cytology; D002113:Calcification, Physiologic; D051379:Mice; D018345:Mice, Knockout; D013961:Thyroid Gland / Q000502:physiology*; D037021:Thyroid Hormone Receptors alpha / Q000172:deficiency / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000172:deficiency / Q000235:genetics
chemical_list: D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta