Disruption of the HPT-axis during growth profoundly influences skeletal development and effects may not be reversed fully following correction of thyroid status. Adult thyrotoxicosis leads to increased bone turnover and is an established risk factor for osteoporotic fracture. The conventional view that skeletal responses to abnormal thyroid status result solely from altered T3 action in bone has, however, been questioned by studies proposing TSH as a negative regulator of bone turnover. Osteoblasts and osteoclasts were found to express the TSH receptor (TSHR) whilst characterization of TSHR null mice revealed high bone turnover osteoporosis. These findings were interpreted to indicate that bone loss in thyrotoxicosis results from TSH deficiency. This model is, however, inconsistent with the increased risk of osteoporotic fracture seen in Graves disease, in which TSHR stimulating antibodies are pathognomonic. Studies in genetically modified mice in which the HPT-axis or the action of T3 is disrupted have addressed the relative importance of T3 and TSH action in bone. Mutation of thyroid hormone receptor α (TRα), the predominant TR isoform in bone, results in decreased T3 action in bone but does not affect systemic thyroid status. Delayed ossification and increased bone mass in these animals indicates that responses to reduced T3 action in bone predominate when TSH levels are normal. Similarly, mutation of TRβ results in increased T3 action in bone and increased levels of TSH. Accelerated ossification and osteoporosis in these animals confirms that effects of T3 excess predominate even when TSH levels are also increased. The similar skeletal phenotypes in Pax8−/− and hyt/hyt mice, in which severe T3 deficiency is accompanied by extremes of TSH action, demonstrate that during development the effects of T3 deficiency are independent of TSHR activity. Together, these studies suggest that skeletal responses to hypo- and hyperthyroidism are mediated by T3 acting via TRα.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology