Endocrine Abstracts (2006) 11 OC50

Congenitally hypothyroid mice with (Pax8−/−) or without (hyt/hyt) functional TSH receptors (TSHR) display equivalent skeletal phenotypes

GR Williams1, R Swinhoe1, E Murphy1, AJ Williams1, S Costagliola2, G Vassart2, PGT Howell3, A Boyde4, F Flamant5, J Samarut5, R Weiss6, S Refetoff7 & JHD Bassett1


1Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom; 2Institut de Recherche Interdisciplinaire (IRIBHM) and Department of Medical Genetics, Universite Libre de Bruxelles, Brussels, Belgium; 3Eastman Dental Institute, University College London, London, United Kingdom; 4Centre for Oral Growth and Development, Queen Mary, University of London, London, United Kingdom; 5Laboratoire de Biologie Moléculaire et Cellulaire de l’Ecole Normale Supérieure de Lyon, Lyon, France; 6Department of Medicine, The University of Chicago, Chicago, United States; 7Departments of Medicine, Pediatrics, and Committee on Genetics, The University of Chicago, Chicago, United Kingdom.


Studies of TSHR−/− mice suggest that TSH inhibits bone turnover, but these mice have congenital hypothyroidism and the actions of TSH cannot be separated from effects of thyroid hormone deficiency. We characterised skeletal development in hyt/hyt mice, which have a point mutation in the Tshr gene, and Pax8−/− mice with thyroid gland agenesis. Hyt/hyt mice have a 100-fold increase in TSH but inactive TSHRs, whereas Pax8−/− mice have a 400-fold increase in TSH and functional TSHRs. Bone length was reduced by 16% in 7 week-old hyt/hyt mice (P<0.01) but heterozygotes were similar to WT. Growth plates from hyt/hyt mice showed an increase in total width (P<0.05), reserve and proliferative zones (P<0.05), disorganised proliferating chondrocytes columns and an indistinct hypertrophic zone. This delay in endochondral ossification was association with a 35% reduction in cortical bone thickness (P<0.001). DXA bone mineral density (BMD) was reduced by 15% (P<0.05) and bone volume fraction (BVF) by 9% (P<0.05). BMD and BVF in heterozygotes were no different to WT, but quantitative backscattered electron scanning electron microscopy revealed a clear reduction in bone micro-mineralisation density in both hyt/hyt and heterozygote mice (P<0.01). Bone length was reduced by 19% at 2 weeks (P<0.01) and 7% at 10 weeks in Pax8−/− mice (P<0.05). Growth plates from Pax8−/− mice showed an increase in total width (P<0.001), reserve and proliferative zones (P<0.05) and disorganisation of the proliferating chondrocytes columns and hypertrophic zone. Cortical bone thickness was reduced by 31% (P<0.05). DXA-BMD was reduced by 5% (ns) but micro-mineralisation density was markedly reduced in Pax8−/− mice (P<0.001) indicating that defects of bone mineralisation were similar in hyt/hyt and Pax8−/− mice. These studies demonstrate that the skeletal phenotype of congenital hypothyroidism is largely independent of TSH action, suggesting that the hypothalamic-pituitary-thyroid axis physiologically regulates endochondral ossification via the actions of T3.