Endocrine Abstracts

T3 is essential for skeletal development and its actions are mediated by two nuclear receptors (TRs), with TR alpha (TRa) being functionally predominant in bone. The TRa1 isoform binds T3 with high affinity and activates target gene expression in response to hormone. TRa2, however, does not bind T3 or regulate transcription in response to hormone. Intriguingly, TRa2 is expressed at high levels from early in development in all tissues and is conserved in all mammals, although its physiological role is unknown. To investigate the function of TRa2, we characterised the skeleton in TRa2-null mice (TRa2-/-). A gross delay in frontal, parietal and interparietal bone formation was evident from embryonic day 17.5. This was associated with severely delayed closure of the cranial sutures leading to brachycephaly (cephalic index (skull width/length) 83% vs 79% vs 73%; TRa2-/-vs TRa2+/- vs wild-type) at 2 weeks. Dysplasia of the clavicles was also observed as early as E17.5, but was maximal at birth with an increased clavicular angle of 13 degrees in TRa2-/- compared with TRa2+/- and wild-type littermates (P=0.02). These findings are typical features of the human cleidocranial dysplasias and indicate a defect in intramembranous ossification. TRa2-/- mice also exhibited features of abnormal endochondral bone formation. Metacarpophalangeal and metatarsophalangeal ossification was delayed as early as E17.5. Growth retardation was evident from birth and persisted until 4 weeks of age with the maximal difference seen at 3 weeks (TRa2-/-: -11%, P=0.001; TRa2+/-: -3%, P=0.055 versus wild-type). Histological analysis of tibial growth plate architecture and regional organisation revealed a delay in hypertrophic chondrocyte differentiation of approximately 2 weeks. Such abnormalities of endochondral ossification are also well-recognised features of the cleidocranial dysplasias. These studies indicate that the correct ratio of TRa1 to TRa2 expression is essential for normal skeletal development.