Endocrine Abstracts

Thyroid hormone (T3) is required for skeletal development during childhood and T3 regulates bone turnover and mineralisation in adults. Thyrotoxicosis is an established risk factor for osteoporosis. We and others have shown that T3 receptors (TRs) are expressed in osteoblasts and growth plate chondrocytes, which represent primary T3-target cells in the skeleton. T3 effects on osteoclast-mediated bone resorption are thought to be mediated by osteoblasts via paracrine pathways. Nevertheless, the mechanism of T3-action in bone is poorly understood. We analysed skeletal development in TRalpha0/0 mice, which lack all products of the TRalpha gene, and TRbetaPV mice, which harbour a mutation in the TRbeta gene that causes severe resistance to thyroid hormone. TRalpha0/0 mice are biochemically euthyroid and have normal levels of growth hormone production. They exhibit a phenotype of delayed endochondral ossification and reduced bone mineralisation. TRbeta-null mice display no skeletal phenotype. Homozygous TRbetaPV mutant mice have severe disruption of the pituitary-thyroid axis with circulating T4 and T3 levels increased 9-15 fold and TSH levels elevated greater than 400-fold. Surprisingly, they exhibit advanced endochondral and intramembranous ossification with increased bone mineralisation. In further studies, we identified that fibroblast growth factor receptor-1 (FGFR1) expression and functional activity are stimulated by T3 in bone. FGFR1 expression and T3-stimulated functional activity was reduced in osteoblasts from TRalpha0/0 mice whereas its expression was increased in bone from TRbetaPV mice. These data suggest that TRalpha0/0 mice exhibit a hypothyroid phenotype in bone, whereas in TRbetaPV mice the phenotype reflects a thyrotoxic skeleton. These data indicate that TRalpha is the major functional TR in bone in vivo and suggest that important T3-effects on bone are mediated via a novel pathway involving activation of FGFR1. Genetically modified mice are a powerful resource that will allow further elucidation of the mechanism of T3 action in bone.