Thyroid status during skeletal development determines adult bone structure and mineralization.
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.
Bassett
J H Duncan
JH
Molecular Endocrinology Group, MRC Clinical Sciences Center, Hammersmith Hospital, London W12 0NN, United Kingdom.
Nordström
Kristina
K
Boyde
Alan
A
Howell
Peter G T
PG
Kelly
Shane
S
Vennström
Björn
B
Williams
Graham R
GR
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
D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta