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

作者：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 E; Zorn Telma M; Brum Patricia C; Gouveia Cecilia H^*

来源：Journal of Bone and Mineral Research, 2011, 26(3): 591-603.

DOI：10.1002/jbmr.243

• SYMPATHETIC HYPERACTIVITY
• BONE METABOLISM
• BONE MASS
• SNS
• ADRENERGIC RECEPTORS

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.

• 出版日期2011-3