Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype.

TY - JOUR

T1 - Double disruption of α2A- and α2C-adrenoceptors results in sympathetic hyperactivity and high-bone-mass phenotype.

AU - Fonseca, Tatiana L

AU - Jorgetti, Vanda

AU - Costa, Cristiane C

AU - Capelo, Luciane P

AU - Covarrubias, Ambart E

AU - Moulatlet, Ana C

AU - Teixeira, Marilia B

AU - Hesse, Eric

AU - Morethson, Priscilla

AU - Beber, Eduardo H

AU - Freitas, Fatima R

AU - Wang, Charles C

AU - Nonaka, Keico O

AU - Oliveira, Ricardo

AU - Casarini, Dulce E

AU - Zorn, Telma M

AU - Brum, Patricia C

AU - Gouveia, Cecilia H

PY - 2011

Y1 - 2011

N2 - Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via ?(2)-adrenoceptor (?2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, ?(2A)-AR and ?(2C)-AR (?(2A) /?(2C)-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In ?(2A) /?(2C)-ARKO versus wild-type (WT) mice, micro-computed tomographic (µCT) 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-?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 ?(2)-AR mRNA expression also was similar in KO and WT littermates, whereas ?(2A)-, ?(2B)- and ?(2C)-AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected ?(2A)-, ?(2B)-, ?(2C)- and ?(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 ?(2)-AR agonist clonidine and to the nonspecific ?-AR antagonist phentolamine. These findings suggest that ?(2)-AR is not the single adrenoceptor involved in bone turnover regulation and show that ?(2)-AR signaling also may mediate the SNS actions in the skeleton.

AB - Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via ?(2)-adrenoceptor (?2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, ?(2A)-AR and ?(2C)-AR (?(2A) /?(2C)-ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In ?(2A) /?(2C)-ARKO versus wild-type (WT) mice, micro-computed tomographic (µCT) 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-?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 ?(2)-AR mRNA expression also was similar in KO and WT littermates, whereas ?(2A)-, ?(2B)- and ?(2C)-AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected ?(2A)-, ?(2B)-, ?(2C)- and ?(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 ?(2)-AR agonist clonidine and to the nonspecific ?-AR antagonist phentolamine. These findings suggest that ?(2)-AR is not the single adrenoceptor involved in bone turnover regulation and show that ?(2)-AR signaling also may mediate the SNS actions in the skeleton.

KW - Animals

KW - Female

KW - Mice

KW - Mice, Knockout

KW - Phenotype

KW - Osteogenesis/drug effects

KW - Adrenergic alpha-2 Receptor Agonists/pharmacology

KW - Bone Resorption/blood/complications/genetics

KW - Bone and Bones/drug effects/metabolism/pathology

KW - Brain/drug effects/metabolism

KW - Estradiol/blood

KW - Gene Deletion

KW - Gene Expression Regulation/drug effects

KW - Hyperkinesis/blood/complications/pathology

KW - Leptin/blood

KW - Myocardium/metabolism

KW - Nerve Tissue Proteins/metabolism

KW - Norepinephrine/blood

KW - Organ Size/drug effects

KW - Osteoclasts/drug effects/pathology

KW - Receptors, Adrenergic, alpha-2/metabolism

KW - Sympathetic Nervous System/drug effects/pathology

KW - Animals

KW - Female

KW - Mice

KW - Mice, Knockout

KW - Phenotype

KW - Osteogenesis/drug effects

KW - Adrenergic alpha-2 Receptor Agonists/pharmacology

KW - Bone Resorption/blood/complications/genetics

KW - Bone and Bones/drug effects/metabolism/pathology

KW - Brain/drug effects/metabolism

KW - Estradiol/blood

KW - Gene Deletion

KW - Gene Expression Regulation/drug effects

KW - Hyperkinesis/blood/complications/pathology

KW - Leptin/blood

KW - Myocardium/metabolism

KW - Nerve Tissue Proteins/metabolism

KW - Norepinephrine/blood

KW - Organ Size/drug effects

KW - Osteoclasts/drug effects/pathology

KW - Receptors, Adrenergic, alpha-2/metabolism

KW - Sympathetic Nervous System/drug effects/pathology

M3 - SCORING: Journal article

VL - 26

SP - 591

EP - 603

JO - J BONE MINER RES

JF - J BONE MINER RES

SN - 0884-0431

IS - 3

M1 - 3

ER -