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Evaluation of the interaction between thyroid hormone and the sympathetic nervous system, via alpha 2 adrenoceptors, on the regulation of bone growth and maturation


One of the most important findings of the recent years is that bone remodeling is under control of the central nervous system (SNC), with the sympathetic nervous system (SNS) acting as the peripheral effector. A series of studies suggests that the SNS negatively regulates bone mass, acting exclusively via beta 2-adrenoceptor (B2-AR), which is expressed in osteoblasts. However, a recent study of our group demonstrated that mice with double gene inactivation of the adrenoceptor alpha2A and alpha2C (a2A /a2C -AR-/-) present a phenotype of high bone mass (HBM), in spite of presenting chronic sympathetic hyperactivity and intact B2-AR. Furthermore, we demonstrated that these knockout (KO) mice are resistant to the thyroid hormone (TH)-induced osteopenia. In addition, we found that mice with single inactivation of a2A-AR or a2C-AR are resistant to the lower longitudinal bone growth induced by thyrotoxicosis. By immunohistochemistry, we detect that both a2A-AR and a2C-AR are expressed in the bone tissue, in the chondrocytes of the reserve and hypertrophic zones of the epiphyseal growth plates (EGP) and in the hypertrophic chondrocytes of the secondary ossification centers of mice. These findings strongly suggest that (i) B2-AR is not the sole adrenoceptor involved in the control of bone metabolism and that (ii) the SNS interacts with TH to regulate not only the bone mass, but also the longitudinal bone growth. Besides, our findings raise the hypothesis that (i) a2A-AR and/or a2C-AR also present an important role in mediating the actions of the SNS in the skeleton and that (ii) these receptors are involved in the TH-SNS interaction to regulate bone metabolism, growth and development. In the present project, we aim to (i) evaluate if the isolated inactivation of a2A-AR and a2C-AR and if the double inactivation of these receptors interfere in the longitudinal bone growth and in the endochondral and intramembranous ossificafication; (ii) characterize the phenotype of the EGP of a2A-AR-/-, a2C-AR-/- and a2A /a2C -AR-/- mice; (iii) evaluate if the action of TH on bone longitudinal growth depends on a2A-AR and/or a2C-AR, analyzing the effect of TH on the EGP structure and on bone growth of a2A-AR-/-, a2C-AR-/- and a2A /a2C -AR-/- mice; (iv) analyze if known pathways of TH action in the EGP (GH/IGF-1 and Wnt/Beta-catenine pathways) are affected by the isolated inactivation of a2A-AR or a2C-AR or by the double inactivation of these receptors (a2A/C-AR-/-); (v) evaluate if the TH action in the endochondral and intramembranous ossification depends on a2A-AR and/or a2C-AR. We believe that this study will bring new and important information regarding the mechanisms through which TH regulates skeletal bone growth and development. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FONSECA, TATIANA L.; TEIXEIRA, MARILIA B. C. G.; RODRIGUES-MIRANDA, MANUELA; SILVA, MARCOS V.; MARTINS, GISELE M.; COSTA, CRISTIANE C.; ARITA, DANIELLE Y.; PEREZ, JULIANA D.; CASARINI, DULCE E.; BRUM, PATRICIA C.; GOUVEIA, CECILIA H. A. Thyroid hormone interacts with the sympathetic nervous system to modulate bone mass and structure in young adult mice. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 307, n. 4, p. E408-E418, AUG 15 2014. Web of Science Citations: 7.

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