Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta.
Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.
O'Shea
Patrick J
PJ
Molecular Endocrinology Group, 5th Floor Clinical Research Building, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
Bassett
J H Duncan
JH
Sriskantharajah
Srividya
S
Ying
Hao
H
Cheng
Sheue-yann
SY
Williams
Graham R
GR
D000818:Animals; D015519:Bone Density / Q000235:genetics; D001846:Bone Development / Q000235:genetics*; D001842:Bone and Bones / Q000737:chemistry / Q000166:cytology; D016368:Frameshift Mutation; D006980:Hyperthyroidism / Q000235:genetics* / Q000378:metabolism; D007037:Hypothyroidism / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D010902:Pituitary Gland / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000032:analysis / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta / Q000032:analysis / Q000235:genetics*; D014284:Triiodothyronine / Q000378:metabolism
D011986:Receptors, Somatotropin; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D017526:Receptor, IGF Type 1