Double Disruption of alpha(2A)- and alpha(2C)-Adrenoceptors Results in Sympathetic Hyperactivity and High-Bone-Mass Phenotype

Double Disruption of alpha(2A)- and alpha(2C)-Adrenoceptors Results in Sympathetic Hyperactivity and High-Bone-Mass Phenotype

Author Fonseca, Tatiana L. Google Scholar
Jorgetti, Vanda Google Scholar
Costa, Cristiane C. Google Scholar
Capelo, Luciane P. Google Scholar
Covarrubias, Ambart E. Google Scholar
Moulatlet, Ana C. Google Scholar
Teixeira, Marilia B. Google Scholar
Hesse, Eric Google Scholar
Morethson, Priscilla Google Scholar
Beber, Eduardo H. Google Scholar
Freitas, Fatima R. Google Scholar
Wang, Charles C. Google Scholar
Nonaka, Keico O. Google Scholar
Oliveira, Ricardo Google Scholar
Casarini, Dulce Elena Autor UNIFESP Google Scholar
Zorn, Telma M. Google Scholar
Brum, Patricia C. Google Scholar
Gouveia, Cecilia H. Google Scholar
Institution Universidade de São Paulo (USP)
Hannover Med Sch
Universidade Federal de São Carlos (UFSCar)
RDO Diagnost Med
Universidade Federal de São Paulo (UNIFESP)
Abstract Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via beta(2)-adrenoceptor (beta(2)-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, alpha(2A)-AR and alpha(2C)-AR(alpha(2A)/alpha(2C)-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. in alpha(2A)/alpha(2C)-ARKO versus wild-type (WT) mice, micro-computed tomographic (mu CT) analysis showed increased, better connected, and more plate-shaped trabeculae in the femur and vertebra and increased cortical thickness in the vertebra, whereas biomechanical analysis showed increased tibial and femoral strength. Tibial mRNA expression of tartrate-resistant acid phosphatase (TRACP) and receptor activator of NF-kappa B (RANK), which are osteoclast-related factors, was lower in knockout (KO) mice. Plasma leptin and brain mRNA levels of cocaine amphetamine-regulated transcript (CART), which are factors that centrally affect bone turnover, and serum levels of estradiol were similar between mice strains. Tibial beta(2)-AR mRNA expression also was similar in KO and WT littermates, whereas alpha(2A)-, alpha(2B)- and alpha(2C)-AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected alpha(2A)-, alpha(2B)-, alpha(2C)- and beta(2)-ARs in osteoblasts, osteoclasts, and chondrocytes of 18.5-day-old mouse fetuses and 35-day-old mice. Finally, we showed that isolated osteoclasts in culture are responsive to the selective alpha(2)-AR agonist clonidine and to the nonspecific alpha-AR antagonist phentolamine. These findings suggest that beta(2)-AR is not the single adrenoceptor involved in bone turnover regulation and show that alpha(2)-AR signaling also may mediate the SNS actions in the skeleton. (c) 2011 American Society for Bone and Mineral Research.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number FAPESP: 05/59557-8
FAPESP: 06/52982-8
FAPESP: 08/50059-3
FAPESP: 03/07327-3
Date 2011-03-01
Published in Journal of Bone and Mineral Research. Malden: Wiley-Blackwell, v. 26, n. 3, p. 591-603, 2011.
ISSN 0884-0431 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 591-603
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000287827600020

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