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Title: Double Disruption of alpha(2A)- and alpha(2C)-Adrenoceptors Results in Sympathetic Hyperactivity and High-Bone-Mass Phenotype
Authors: Fonseca, Tatiana L.
Jorgetti, Vanda
Costa, Cristiane C.
Capelo, Luciane P.
Covarrubias, Ambart E.
Moulatlet, Ana C.
Teixeira, Marilia B.
Hesse, Eric
Morethson, Priscilla
Beber, Eduardo H.
Freitas, Fatima R.
Wang, Charles C.
Nonaka, Keico O.
Oliveira, Ricardo
Casarini, Dulce Elena [UNIFESP]
Zorn, Telma M.
Brum, Patricia C.
Gouveia, Cecilia H.
Universidade de São Paulo (USP)
Hannover Med Sch
Universidade Federal de São Carlos (UFSCar)
RDO Diagnost Med
Universidade Federal de São Paulo (UNIFESP)
Issue Date: 1-Mar-2011
Publisher: Wiley-Blackwell
Citation: Journal of Bone and Mineral Research. Malden: Wiley-Blackwell, v. 26, n. 3, p. 591-603, 2011.
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.
ISSN: 0884-0431
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