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Study of the effect of thyroid hormone on the morphology of epiphyseal growth plate of mice with double deletion gene receptor alpha 2A and 2C adrenergic

Grant number: 15/07623-9
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2015
Effective date (End): December 31, 2015
Field of knowledge:Biological Sciences - Biology
Principal Investigator:Cecilia Helena de Azevedo Gouveia
Grantee:Iasmin Ferreira de Araujo
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

One 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 b2-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 a2A and a2C (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 ±2A-AR or ±2C-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 double inactivation of these receptors interfere in the longitudinal bone growth; (ii) characterize the phenotype of the EGP of a2A /a2C -AR-/- mice and (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 /a2C -AR-/- mice. We believe that this study will bring new and important information regarding the mechanisms through which TH regulates skeletal bone growth and development.