title: Deletion of β-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation.
abstract: As they age, mice deficient for the β2-adrenergic receptor (Adrb2(-/-) ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of β1-adrenergic receptor signaling and its interaction with β2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for β1-adrenergic receptors and/or β2-adrenergic receptors. Upon axial compression loading of the tibia, bone density, cancellous and cortical microarchitecture, as well as histomorphometric bone forming indices, were increased in both Adrb2(-/-) and wild-type (WT) mice, but not in Adrb1(-/-) nor in Adrb1b2(-/-) mice. Moreover, in the unstimulated femur and vertebra, bone mass and microarchitecture were increased in Adrb2(-/-) mice, whereas in Adrb1(-/-) and Adrb1b2(-/-) double knockout mice, femur bone mineral density (BMD), cancellous bone volume/total volume (BV/TV), cortical size, and cortical thickness were lower compared to WT. Bone histomorphometry and biochemical markers showed markedly decreased bone formation in Adrb1b2(-/-) mice during growth, which paralleled a significant decline in circulating insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3). Finally, administration of the β-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-κB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2(-/-) mice. Altogether, these results demonstrate that β1- and β2-adrenergic signaling exert opposite effects on bone, with β1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas β2-adrenergic receptor signaling mainly regulates bone resorption during aging.
authors.affiliation: Service of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Dominique D
authors.initials: DD
authors.lastname: Pierroz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonnet
authors.forename: Estelle N
authors.initials: EN
authors.lastname: Bianchi
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
authors.forename: René
authors.initials: R
authors.lastname: Rizzoli
authors.forename: Serge L
authors.initials: SL
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005269:Femur / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D018342:Receptors, Adrenergic, beta-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: C547788:Adrb1 protein, mouse; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D007334:Insulin-Like Growth Factor I; D007545:Isoproterenol