GH substitution reverses the growth phenotype but not the defective ossification in thyroid hormone receptor alpha 1-/-beta-/- mice

Thyroid hormone receptor alpha1, beta1 and beta2-deficient mice (TR alpha1- /-beta-/- mice) demonstrate growth retardation and defective ossification i n the epiphyses associated with an inhibition of the GH/IGF-I axis. There a re differences between TR alpha1-/-beta-/- mice (receptor deficient) and th e hypothyroid annual model (ligand deficient). Such differences include pos sible repressive actions exerted by unliganded receptors in the ligand-defi cient (hypothyroid) model but not in the receptor-deficient model. In the p resent study we have investigated whether or not GH substitution rescues th e skeletal phenotype of TR alpha1-/-beta-/- mice. TR alpha1-/-beta-/- and wild-type (WT) mice were treated with GH from day 1 8 until 10 weeks of age. GH substitution of mutant mice resulted in a signi ficant and sustained stimulatory effect on the body weight that was not see n in WT mice. GH-treated mutant mice but not GH-treated WT mice demonstrate d increased length and periosteal circumference of the femur. However, GH s ubstitution did not reverse the defective ossification seen in TR alpha1-/- beta-/- mice. TR alpha1-/-beta-/- mice displayed increased width of the pro ximal tibial growth plate, which was caused by increased width of the proli ferative but not the hypertrophic layer, GH substitution did not restore th e disturbed morphology of the growth plate in TR alpha1-/-beta-/- mice. In summary, GH substitution reverses the growth phenotype but not the defec tive ossification in TR alpha1-/-beta-/- mice. Our data suggest that TRs ar e of importance both for the regulation of the GH/IGF-I axis and for direct effects on cartilage.