The Skeletal Phenotypes of TRalpha and TRbeta Mutant Mice

Analysis of mice harbouring deletions or mutations of T(3) receptor alpha (TRalpha) and beta (TRbeta) have clarified the complex relationship between central and peripheral thyroid status and emphasised the essential but contrasting roles of T(3) in skeletal development and adult bone. These studies indicate that TRalpha1 is the predominant TR expressed in bone and that T(3) exerts anabolic actions during growth but catabolic actions in the adult skeleton. Examination of key skeletal regulatory pathways in TR mutant mice has identified GH, IGF-1 and fibroblast growth factor signalling and the Indian hedgehog/parathyroid hormone-related peptide feedback loop as major targets of T(3) 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 T(3) has direct actions in osteoclasts. Detailed future analysis of the molecular mechanisms of T(3) action in bone will enhance our understanding of this emerging field and has the potential to identify novel strategies for the prevention and treatment of osteoporosis.