Endocrine Abstracts

Background: Thyroid hormone (TH) action is mediated by TH receptors (TRs) α&β. Both regulate gene expression by binding TREs on the DNA (canonical signaling) or activate cellular signaling pathways (noncanonical signaling). Bone is a major TH target and noncanonical TR α & β effects on bone metabolism were suggested. We studied mouse model bones to distinguish between signaling types.

Methods: Growth of WT mice and mice with either knockout (TRαKO, TRβKO) or selective loss of canonical action (TRαGS, TRβGS) was recorded until P112. Femurs and caudal vertebrae were analysed with Faxitron-X-ray-microradiography (BMC, bone length) and high resolution μ-CT (cortical/trabecular thickness, BMD). 3-point-bend testing to destruction with a 100 N load cell revealed yield, maximal and fracture load.

Results: Longitudinal growth of TRαKO and TRαGS mice was equally delayed and normalized after postnatal week 8. Caudal vertebrae height did not differ between genotypes at P112. Trabecular bone stretched farther in TRαKO and TRαGS femurs than in WT (39% & 41% vs. 33%). Trabecular number and connectivity density were increased in both mutants, while spacing was reduced. Trabecular thickness was similar in all groups, as were cortical parameters and BMD. TRα mutant bones contained a dense and more extensive network of normally shaped trabecular bone. No difference was found in yield or fracture load. After T3 treatment, structural differences between TRα mutants and WT were similar. Growth of TRβKO and TRβGS did not differ from WT. T4 serum concentration was elevated in both models due to abolished negative feedback in the HPT axis. BMC was equally reduced in mutant femurs with thinner cortical bone. There were no differences in trabecular parameters.

Conclusion: Adult mice without canonical but preserved noncanonical TRα action showed the TRα knockout phenotype. Thus, these results demonstrate that TH effects in bone are predominantly mediated by canonical TRα action.