Thyroid hormone interacts with the sympathetic nervous system to modulate bone mass and structure in young adult mice

To investigate whether thyroid hormone (TH) interacts with the sympathetic nervous system (SNS) to modulate bone mass and structure, we studied the effects of daily T₃ treatment in a supraphysiological dose for 12 wk on the bone of young adult mice with chronic sympathetic hyperactivity owing to double-gene disruption of adrenoceptors that negatively regulate norepinephrine release, α_2A-AR, and α_2C-AR (α_2A/2C-AR^-/- mice). As expected, T₃ treatment caused a generalized decrease in the areal bone mineral density (aBMD) of WT mice (determined by DEXA), followed by deleterious effects on the trabecular and cortical bone microstructural parameters (determined by μCT) of the femur and vertebra and on the biomechanical properties (maximum load, ultimate load, and stiffness) of the femur. Surprisingly, α_2A/2C-AR^-/- mice were resistant to most of these T₃-induced negative effects. Interestingly, the mRNA expression of osteoprotegerin, a protein that limits osteoclast activity, was upregulated and downregulated by T3 in the bone of α_2A/2C-AR^-/- and WT mice, respectively. β₁-AR mRNA expression and IGF-I serum levels, which exert bone anabolic effects, were increased by T₃ treatment only in α_2A/2C-AR^-/- mice. As expected, T₃ inhibited the cell growth of calvaria-derived osteoblasts isolated from WT mice, but this effect was abolished or reverted in cells isolated from KO mice. Collectively, these findings support the hypothesis of a TH-SNS interaction to control bone mass and structure of young adult mice and suggests that this interaction may involve α₂-AR signaling. Finally, the present findings offer new insights into the mechanisms through which TH regulates bone mass, structure, and physiology.