An important finding of the recent years is that bone remodelling is under control of the central nervous system (CNS), with the sympathetic nervous system (SNS) acting as the peripheral effector. Evidence suggests that the SNS negatively regulates bone mass via β2-adrenergic receptor (AR-β2), which is expressed in osteoblasts. However, previous research by our group has demonstrated that mice with double inactivation of α2A and α2C adrenergic receptors (α2A/α2C-AR-/-) exhibit a high bone mass phenotype (HBM), in spite of presenting chronic sympathetic hyperactivity and intact β2-AR. By immunohistochemistry, we showed that α2A and α2C adrenergic receptors (α2C-AR and α2A-AR) are expressed in osteoblasts, osteocytes, osteoclasts and in chondrocytes of the epiphyseal growth plate (EGP), of the secondary ossification centers and of the articular cartilage, which suggests that α2 adrenergic receptors also mediate the actions of the SNS in the skeleton. We also found that α2A/α2C-AR-/- mice are resistant to the thyroid hormone (TH) excess-induced osteopenia and that mice with the single inactivation of α2A-AR or α2C-AR are resistant to the reduction of bone longitudinal growth caused by thyrotoxicosis. These findings suggest that TH interacts with the SNS, through α2-AR signalling to regulate bone metabolism and growth. The present study aimed to investigate the role α2A-AR and the possible interaction between the SNS and TH to regulate the longitudinal bone growth (LBG). Thus, we evaluated the bone growth and the morphology of the femoral EGP of 21-day old female wild-type (WT) and α2AAR-/- mice (n=8/group), treated for four weeks with a supraphysiological dose of triiodothyronine (7 μg/100gBW/day), to mimic hyperthyroidism (Hyper), or treated with inhibitory drugs of the thyroid function, methimazole (0.1%) and sodium perchlorate (1%), added to drinking water, for hypothyroidism (Hypo) induction. Compared with WT mice, euthyroid α2AAR-/- mice showed lower femur length; an important disorganisation of the proliferative zone (PZ) with the presence of lacunae between the columns of chondrocytes; and a significant decrease (84%, p<0.001) in the thickness of the hypertrophic chondrocytes zone (HZ) of the EGP. In WT animals, Hypo promoted expected alterations: a significant reduction in the LBG, PZ disorganisation and a decreased thickness of HZ. Surprisingly, Hypo had no effect on the EGP of α2AAR-/-. On the other hand, Hyper caused an increase in the thickness of the reserve zone (RZ) in α2AAR-/- mice, but not in WT mice. These findings support the hypothesis that the SNS regulates the LBG via α2AAR and that a TH-SNS interaction can regulate this process.
Disclosure: The authors declared no competing interests. This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (grant number 2013/02247-3).