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

Abstract

Thyroid hormone (T3) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T3 receptor βPV (TRβPV) mice in which a targeted frameshift mutation in TRβ results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRα1PV mice in which the same PV mutation was targeted to TRα1. In contrast to TRβPV mice, TRα1PV 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 TRα1PV 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 TRβPV mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T3 action in bone in vivo. The divergent phenotypes observed in TRα1PV and TRβPV mice arise because the pituitary gland is a TRβ-responsive tissue, whereas bone is TRα responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status. Copyright © 2005 by The Endocrine Society.