Deletion of b-adrenergic receptor 1, 2, or both leads to different bone phenotypes and responses to mechanical stumulation.
As they age, mice deficient for the beta2-adrenergic receptor (Adrb2(-/-) ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of beta1-adrenergic receptor signaling and its interaction with beta2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for beta1-adrenergic receptors and/or beta2-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 beta-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-kappaB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2(-/-) mice. Altogether, these results demonstrate that beta1- and beta2-adrenergic signaling exert opposite effects on bone, with beta1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas beta2-adrenergic receptor signaling mainly regulates bone resorption during aging.
|Authors||Pierroz, D.D.; Bonnet, N.; Bianchi, E.N.; Bouxsein, M.L.; Baldock, P.A.; Rizzoli, R. Ferrari, S.L.|
|Publisher Name||JOURNAL OF BONE AND MINERAL RESEARCH|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22407956|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11526|