Alteration of Trabecular Bone under Chronic β2 Agonists Treatment

Bonnet, Nicolas; Brunet-Imbault, B.; Arlettaz, A.; Horcajada, Marie‐Noëlle; Collomp, K.; Benhamou, Claude Laurent; Courteix, Daniel

doi:10.1249/01.mss.0000177592.82507.95

Cited by 44 publications

(30 citation statements)

References 31 publications

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“…Lack of Dopamine beta-hydroxylase (Dbh), the enzyme generating norepinephrine (NE), induced a late onset increase in bone mass [7]. In agreement with this result, mice and rats treated with the nonselective beta-adrenergic blocker propranolol exhibited an increased bone mass, whereas mice treated with the non-selective beta-agonist isoproterenol or the β2AR selective agonists clenbuterol or salbutamol exhibited a low bone mass [7,19]. Together, these results demonstrated that the sympathetic nervous system controls bone formation via βAR in osteoblasts in vivo.…”

Section: The Sympathetic Nervous System Links Leptin-responsive Hypotmentioning

confidence: 73%

Regulation of bone remodeling by the central and peripheral nervous system

Elefteriou

2008

Archives of Biochemistry and Biophysics

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150

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The homeostatic nature of bone remodeling has become a notion further supported lately by the demonstration that neuropeptides and their receptors regulate osteoblast and osteoclast function in vivo. Following initial studies reporting the presence of nerves and nerve-derived products within the bone micro-environment and the expression of receptors for these neuropeptides in bone cells, new experimental and mechanistic evidence based on in vivo murine genetic and pharmacologic models recently demonstrated that inputs from the central and peripheral nervous system feed into the already complex regulatory machinery controlling bone remodeling. The function of a number of "osteo-neuromediators" has been characterized, including norepinephrine and the beta 2-adrenergic receptor, Neuropeptide Y and the Y1 and Y2 receptors, endocannabinoids and the CB1 and CB2 receptors, as well as dopamine, serotonin and their receptors and transporters, Calcitonin gene-related peptide, and neuronal NOS. This new body of evidence suggests that neurons in the central nervous system integrate clues from the internal and external milieux, such as energy homeostasis, glycemia or reproductive signals, with the regulation of bone remodeling. The next major tasks in this new area of bone biology will be to understand, at the molecular level, the mechanisms by which common central neural systems regulate and integrate these major physiological functions, the relative importance of the central and peripheral actions of neuropeptides present in both compartments and their relationship, and how bone cells signal back to central centers, because the definition of a homeostatic function implies the existence of feedback signals. Together, these findings shed a new light on the complexity of the mechanisms regulating bone remodeling and uncovered new potential therapeutic strategies for the design of bone anabolic treatments. This review summarizes the latest advances in this area, focusing on investigations based on in vivo animal studies. KeywordsBone; osteoblast; osteoclast; neuron; sympathetic nervous system; hypothalamus; leptin; neuropeptide; adrenergic receptor; neuropeptide Y; endocannabinoid The central nervous system restrains bone formationIt is the association between body weight and bone density as well as the association between loss of gonadal function and osteoporosis that initially pointed to the putative existence of a common factor regulating body weight, reproduction and bone mass. Based on the knowledge that the adipocyte-derived hormone leptin regulates major physiological functions, including body weight and reproduction, via the hypothalamus and its receptor ObRb, it was

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Section: The Sympathetic Nervous System Links Leptin-responsive Hypotmentioning

confidence: 73%

Regulation of bone remodeling by the central and peripheral nervous system

Elefteriou

2008

Archives of Biochemistry and Biophysics

206

150

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“…However, despite some of the positive data that make clenbuterol an attractive option for clinical use, there are number of other potentially dangerous side effects associated with its use or misuse that should not be ignored. Clenbuterol can cause bone loss which, when couple with muscle growth, can increase the risk of fractures for humans (Bonnet et al, 2005). In addition, clenbuterol ingested directly or via contaminated meat from treated animals can be toxic and can lead to a variety of symptoms in humans, including tachycardia, myocardial infarction, distal tremors, hyperglycemia, among other possible symptoms (Brambilla et al, 2000;Hoffman et al, 2001;Kierzkowska et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

β2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals

Ramos

Colgan

Nou

et al. 2008

Neurobiology of Aging

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Previous studies using a mixed β1 and β2 adrenergic antagonist, propanolol, have indicated that β adrenoceptors have little effect on the cognitive functioning of the prefrontal cortex. However, recent studies have suggested that endogenous stimulation of β1 adrenoceptors impairs working memory in both rats and monkeys. Since propanolol has no effect on cognition, we hypothesized that activation of β2 adrenoceptors might improve performance in a working memory task. We tested this hypothesis by observing the effects of the β2 agonist, clenbuterol, on spatial working memory performance. Clenbuterol was either infused directly into the prefrontal cortex (rats) or administered systemically (monkeys). Results demonstrated that clenbuterol improved performance in many young and aged rats and monkeys who performed poorly under control conditions. Actions at β2 adrenoceptors were confirmed by challenging the clenbuterol response with the β2 adrenergic antagonist, ICI 118,551. The effects of clenbuterol were not universal and depended on the cognitive status of the animal: the drug moderately improved only a subset of animals with working memory impairment.

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“…For instance, some studies are considered mice treated with the ␤-blocker propranolol, mice deficient for dopamine ␤-hydroxylase (the step-limiting enzyme responsible for catecholamine synthesis), and leptin-deficient Ob/Ob mice (Elefteriou et al, 2005a,b). On the other hand, mice or rats treated with ␤-agonist isoproterenol or clenbuterol displayed a marked decrease in osteoblast number, activity, trabecular bone microarchitecture parameters, and biomechanical properties (Takeda et al, 2002;Bonnet et al, 2005). Therefore, ␤-blockers has been proposed to overcome the loss of bone mass occurring in postmenopausal women.…”

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confidence: 99%

Dose Effects of Propranolol on Cancellous and Cortical Bone in Ovariectomized Adult Rats

Bonnet

Laroche²,

Vico³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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Animal studies suggest that bone remodeling is under ␤-adrenergic control via the sympathetic nervous system. The purpose of this study was to examine the preventive effect of different doses of nonspecific ␤-blockers (propranolol) on trabecular and cortical bone envelopes in ovariectomized rats. Six-month-old female Wistar rats were ovariectomized (OVX, n ϭ 60) or shamoperated (n ϭ 15). Then, OVX rats were subcutaneously injected with 0.1 (n ϭ 15), 5 (n ϭ 15), or 20 (n ϭ 15) mg/kg propranolol or vehicle (n ϭ 15) for 10 weeks. Tibial and femoral bone mineral density (BMD) were analyzed longitudinally by dual-energy X-ray absorptiometry. At death, the left tibial metaphysis and L 4 vertebrae were removed, and microcomputed tomography (Skyscan 1072; Skyscan, Aartselaar, Belgium) was performed for trabecular bone structure investigation. Histomorphometry analysis was performed on the right proximal tibia to assess bone cell activities. After 10 weeks, OVX rats had decreased BMD and trabecular parameters and increased bone turnover, as well as cortical porosity compared with the sham group (p Ͻ 0.001). Bone architecture alteration was preserved by 0.1 mg/kg propranolol due to higher trabecular number and thickness (ϩ50.35 and ϩ6.81%, respectively, than OVX; p Ͻ 0.001) and lower cortical pore number (Ϫ52.38% than OVX; p Ͻ 0.001). Animals treated by 0.1 mg/kg propranolol had a lower osteoclast surface and a higher osteoblast activity compared with OVX. Animals treated by 20 mg of propranolol did not significantly differ from OVX rats. Animals treated by 5 mg of propranolol have been partially preserved from the ovariectomy. These results showed a dose effect of ␤-blockers. The lower the dose of propranolol breeding, the better the preventive effect against ovariectomy.

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Alteration of Trabecular Bone under Chronic β2 Agonists Treatment

Cited by 44 publications

References 31 publications

Regulation of bone remodeling by the central and peripheral nervous system

Regulation of bone remodeling by the central and peripheral nervous system

β2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals

Dose Effects of Propranolol on Cancellous and Cortical Bone in Ovariectomized Adult Rats

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