Lack of alpha(2C)-Adrenoceptor Results in Contrasting Phenotypes of Long Bones and Vertebra and Prevents the Thyrotoxicosis-Induced Osteopenia

Autor(es)

Cruz Grecco Teixeira, Marilia Bianca ^[1] ; Martins, Gisele Miyamura ^{[1, 2]} ; Miranda-Rodrigues, Manuela ^[1] ; De Araujo, Iasmin Ferreira ^[1] ; Oliveira, Ricardo ^[3] ; Brum, Patricia Chakur ^[4] ; Azevedo Gouveia, Cecilia Helena ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Anat, Inst Biomed Sci, Sao Paulo - Brazil

^[2] Univ Fed Juiz de Fora, Hlth Basic Dept, Juiz De Fora, MG - Brazil

^[3] RDODiagnost Med, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Dept Biodinam Human Body Moviment, Sch Phys Educ & Sport, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 11, n. 1 JAN 27 2016.
• Citações Web of Science: 6

Resumo

A series of studies have demonstrated that activation of the sympathetic nervous system (SNS) causes osteopenia via beta(2)-adrenoceptor (beta(2)-AR) signaling. However, in a recent study, we found an unexpected and generalized phenotype of high bone mass in female mice with chronic sympathetic hyperactivity, due to double gene inactivation of adrenoceptors that negatively regulate norepinephrine release, alpha(2A)-and alpha(2C)-AR (alpha(2A/2C)-AR(-/-)). These findings suggest that beta(2)-AR is not the single adrenoceptor involved in bone turnover regulation and show that alpha(2)-AR signaling may also mediate the SNS actions in the skeleton. In addition, we found that alpha(2A/2C)-AR(-/-) animals are resistant to the thyrotoxicosis-induced osteopenia, suggesting that thyroid hormone (TH), when in supraphysiological levels, interacts with the SNS to control bone mass and structure, and that this interaction may also involve alpha(2)-AR signaling. In the present study, to further investigate these hypotheses and to discriminate the roles of alpha(2)-AR subtypes, we have evaluated the bone phenotype of mice with the single gene inactivation of alpha(2C)-AR subtype, which mRNA expression was previously shown to be down regulated by triiodothyronine (T3). A cohort of 30 day-old female alpha(2C)AR(-/-) mice and their wild-type (WT) controls were treated with a supraphysiological dose of T3 for 30 or 90 days, which induced a thyrotoxic state in both mouse lineages. The microcomputed tomographic (mu CT) analysis showed that alpha(2C)-AR(-/-) mice present lower trabecular bone volume (BV/TV) and number (Tb.N), and increased trabecular separation (Tb.Sp) in the femur compared with WT mice; which was accompanied by decreased bone strength (determined by the three-point bending test) in the femur and tibia. The opposite was observed in the vertebra, where alpha(2C)-AR(-/-) mice show increased BV/TV, Tb.N and trabecular thickness (Tb.Th), and decreased Tb.Sp, compared with WT animals. In spite of the contrasting bone phenotypes of the femur and L5, thyrotoxicosis negatively regulated most of the micro architectural features of the trabecular bone in both skeletal sites of WT, but not of alpha(2C)-AR-/- mice. T3 treatment also decreased biomechanical properties (maximum load and ultimate load) in the femur and tibia of WT, but not of knockout mice. The mRNA expression of osteocalcin, a marker of mature osteoblasts, and tartrate-resistant acid phosphatase, which is expressed by osteoclasts and is involved in collagen degradation, was increased by T3 treatment only in WT, and not in alpha(2C)-AR(-/-) mice. Altogether, these findings suggest that alpha(2C)-AR subtype mediates the effects of the SNS in the bone in a skeletal site-dependent manner, and that thyrotoxicosis depends on alpha(2C)-AR signaling to promote bone loss, which sustains the hypothesis of a TH-SNS interaction to modulate bone remodeling and structure. (AU)

• Processo FAPESP: 10/50068-2 - Avaliação do efeito do hormônio tireoideano na estrutura e fisiologia ósseas de camundongos com inativação do gene do adrenoceptor alfa 2C
• Beneficiário: Marília Bianca Cruz Grecco Teixeira
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 10/06409-0 - Avaliação do efeito do hormônio tireoideano na estrutura e fisiologia óssea de camundongos com inativação dos genes dos adrenoceptores alfa 2A e alfa 2C
• Beneficiário: Cecilia Helena de Azevedo Gouveia
• Modalidade de apoio: Auxílio à Pesquisa - Regular