Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor α1 or β

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) (TR beta(PV)) mice in which a targeted frameshift mutation in TR beta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TR alpha 1(PV) mice in which the same PV mutation was targeted to TR alpha 1. In contrast to TR beta(PV) mice, TR alpha 1(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 TR alpha 1(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 TR alpha 1(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 TR alpha 1(PV) and TR beta(PV) mice arise because the pituitary gland is a TR beta-responsive tissue, whereas bone is TR alpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.