Adrenergic regulation of bone metabolism: Possible involvement of sympathetic innervation of osteoblastic and osteoclastic cells

Togari, Akifumi

doi:10.1002/jemt.10121

Cited by 189 publications

(116 citation statements)

References 73 publications

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“…(52) Later, it was shown that a 2 -ARs are not restricted to presynaptic locations but also have postsynaptic locations and functions, which include regulation of body temperature, intraocular pressure, lipolysis, and pain perception. (53)(54)(55) In accordance with a previous study that identified the presence of a 2 -AR isoforms in human-derived bone cells, (2) we showed that the mRNA of the three known a 2 -AR isoforms, a 2A -, a 2B -, and a 2C -AR, are expressed in the bone of WT mice and in osteoblast-like cells derived from the mouse calvarium (MC3T3-E1 cells). In addition, we found that the mRNA expression of a 2B -AR was downregulated in a 2A /a 2C -ARKO mice compared with WT mice.…”

Section: Discussionsupporting

confidence: 91%

“…We next investigated the mRNA expression of a 2B -AR, which was shown previously to be expressed in human-derived bone cells. (2) We found that a 2B -AR is expressed in the tibias of both a 2A /a 2C -ARKO and WT mice but that its expression is 37% lower in KO animals compared with WT mice (Fig. 5A).…”

Section: Expression Of Adrenoceptors In the Skeleton And Bone Cellsmentioning

confidence: 76%

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

Fonseca

Jorgetti

Costa

et al. 2010

Journal of Bone and Mineral Research

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Evidence demonstrates that sympathetic nervous system (SNS) activation causes osteopenia via b 2 -adrenoceptor (b2-AR) signaling. Here we show that female mice with chronic sympathetic hyperactivity owing to double knockout of adrenoceptors that negatively regulate norepinephrine release, a 2A -AR and a 2C -AR (a 2A /a 2C -ARKO), present an unexpected and generalized phenotype of high bone mass with decreased bone resorption and increased formation. In a 2A /a 2C -ARKO versus wild-type (WT) mice, micro-computed tomographic (mCT) 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-kB (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 b 2 -AR mRNA expression also was similar in KO and WT littermates, whereas a 2A -, a 2B -and a 2C -AR mRNAs were detected in the tibia of WT mice and in osteoblast-like MC3T3-E1 cells. By immunohistochemistry, we detected a 2A -, a 2B -, a 2C -and b 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 a 2 -AR agonist clonidine and to the nonspecific a-AR antagonist phentolamine. These findings suggest that b 2 -AR is not the single adrenoceptor involved in bone turnover regulation and show that a 2 -AR signaling also may mediate the SNS actions in the skeleton. ß

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Section: Discussionsupporting

confidence: 91%

Section: Expression Of Adrenoceptors In the Skeleton And Bone Cellsmentioning

confidence: 76%

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

Fonseca

Jorgetti

Costa

et al. 2010

Journal of Bone and Mineral Research

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“…Bone, in particular trabecular bone, is densely innervated by sympathetic fibers (36)(37)(38), and genetic ablation of adrenergic signaling leads to a high bone mass (27,28). Like the CMSinduced depression, chronic SNS activation and sympathetic agonists inhibit bone formation mainly by decreasing osteoblast number.…”

Section: Discussionmentioning

confidence: 99%

Depression induces bone loss through stimulation of the sympathetic nervous system

Yirmiya¹,

Goshen²,

Bajayo³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

197

138

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Major depression is associated with low bone mass and increased incidence of osteoporotic fractures. However, causality between depression and bone loss has not been established. Here, we show that mice subjected to chronic mild stress (CMS), an established model of depression in rodents, display behavioral depression accompanied by impaired bone mass and structure, as portrayed by decreases in trabecular bone volume density, trabecular number, and trabecular connectivity density assessed in the distal femoral metaphysis and L3 vertebral body. Bone remodeling analysis revealed that the CMS-induced skeletal deficiency is accompanied by restrained bone formation resulting from reduced osteoblast number. Antidepressant therapy, which prevents the behavioral responses to CMS, completely inhibits the decrease in bone formation and markedly attenuates the CMS-induced bone loss. The depression-triggered bone loss is associated with a substantial increase in bone norepinephrine levels and can be blocked by the ␤-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. These results define a linkage among depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating an interaction among behavioral responses, the brain, and the skeleton, which leads to impaired bone structure. Together with the common occurrence of depression and bone loss in the aging population, the present data implicate depression as a potential major risk factor for osteoporosis and the associated increase in fracture incidence.antidepressant ͉ chronic depression ͉ osteoporosis ͉ bone formation ͉ adrenergic signaling

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“…Osteoblasts have been reported to express receptors for several neuropeptides, suggesting that they could indeed integrate multiple neuronal signals (161). Immunolabeling studies have revealed a close association between glutamate-, catecholamine-, or peptide-containing nerve fibers and osteoblasts or osteoclasts in the endosteum (162).…”

Section: Sympathetic Signalingmentioning

confidence: 99%

Signaling and transcriptional regulation in osteoblast commitment and differentiation

Huang

Yang²,

Shao³

et al. 2007

Front Biosci

534

421

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The major event that triggers osteogenesis is the transition of mesenchymal stem cells into bone forming, differentiating osteoblast cells. Osteoblast differentiation is the primary component of bone formation, exemplified by the synthesis, deposition and mineralization of extracellular matrix. Although not well understood, osteoblast differentiation from mesenchymal stem cells is a well-orchestrated process. Recent advances in molecular and genetic studies using gene targeting in mouse enable a better understanding of the multiple factors and signaling networks that control the differentiation process at a molecular level. Osteoblast commitment and differentiation are controlled by complex activities involving signal transduction and transcriptional regulation of gene expression. We review Wnt signaling pathway and Runx2 regulation network, which are critical for osteoblast differentiation. Many other factors and signaling pathways have been implicated in regulation of osteoblast differentiation in a network manner, such as the factors Osterix, ATF4, and SATB2 and the TGF-beta, Hedgehog, FGF, ephrin, and sympathetic signaling pathways. This review summarizes the recent advances in the studies of signaling transduction pathways and transcriptional regulation of osteoblast cell lineage commitment and differentiation. The knowledge of osteoblast commitment and differentiation should be applied towards the development of new diagnostic and therapeutic alternatives for human bone diseases. KeywordsOsteoblast; Runx2; Osterix; ATF4; SATB2; Wnt signaling; TGF-Beta signaling; hedgehog signaling; fgf signaling; ephrin signaling; sympathetic signaling; Review INTRODUCTIONPhysiological bone turnover can be divided into 2 temporal phases: modeling, which occurs during development, and remodeling, a lifelong process involving tissue renewal. Remodeling starts with removal by osteoclasts of matrix, a mixture of insoluble proteins in which type I collagen is predominant (>90%) and a poorly crystalline, chemically modified hydroxyapatite. Following resorption, osteoblasts are recruited to the site, where they secrete and mineralize new matrix. The increased activity of osteoclasts caused by estrogen withdrawal causes bone loss and osteoporosis, a frequent low-bone mass disorder in NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript postmenopausal women leading to structural instability and a high fracture risk. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute (1). Osteoporosis is a factor in more than 1.5 million fractures each year in the United States alone. Costs have been estimated at more than $17 billion a year, particularly from hip fractures, more than 75% of them in women. A better understanding of bone quality, coming from biochemical markers and refined imaging techniques, will help predict who is most at risk of debilitating fractures. One of the main appro...

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Adrenergic regulation of bone metabolism: Possible involvement of sympathetic innervation of osteoblastic and osteoclastic cells

Cited by 189 publications

References 73 publications

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

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

Depression induces bone loss through stimulation of the sympathetic nervous system

Signaling and transcriptional regulation in osteoblast commitment and differentiation

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