MRC Clinical Sciences Centre,

Analysis of mice harbouring deletions or mutations of thyroid hormone receptor α (TRα) and β (TRβ) have clarified the complex relationship between central and peripheral thyroid status and emphasised the essential but contrasting roles of thyroid hormone (T3) in skeletal development and adult bone. These studies indicate that TRα1 is the predominant TR expressed in bone and that T3 exerts anabolic actions during growth but catabolic actions in the adult skeleton. Examination of key skeletal regulatory pathways in TR mutant mice has identified growth hormone, insulin like growth factor 1 and fibroblast growth factor signalling and the Indian hedgehog/parathyroid hormone-related peptide feed back loop as major targets of T3 action in chondrocytes and osteoblasts. Nevertheless, although increased osteoclastic resorption is a major feature of thyrotoxic bone loss and altered osteoclast activity is central to the skeletal phenotype of TR mutant mice, it remains unclear whether T3 has direct actions in osteoclasts. Detailed future analysis of the molecular mechanisms of T3 action in bone will enhance our understanding of this emerging field and has the potential to identify novel strategies for prevention and treatment of osteoporosis