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 b2-adrenergic receptor (Adrb2 À/À ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of b1-adrenergic receptor signaling and its interaction with b2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for b1-adrenergic receptors and/or b2-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 À/À and wild-type (WT) mice, but not in Adrb1 À/À nor in Adrb1b2 À/À mice. Moreover, in the unstimulated femur and vertebra, bone mass and microarchitecture were increased in Adrb2 À/À mice, whereas in Adrb1 À/À and Adrb1b2 À/À 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 À/À 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 b-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-kB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2 À/À mice. Altogether, these results demonstrate that b1-and b2-adrenergic signaling exert opposite effects on bone, with b1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas b2-adrenergic receptor signaling mainly regulates bone resorption during aging. ß

Animal models for osteoporosis

“…In Adrb1 À /À 2 À /À 3 À /À mice, bone volume was increased in cancellous bone of vertebrae and femurs and in cortical bone of femurs at 6 weeks of age and only in cortical bone of femurs at 16 weeks of age due to the reduced bone resorption (Bouxsein et al, 2009). Tibiae from Adrb2 À /À mice but not Adrb1 À /À mice and Adrb1 À /À 2 À /À mice responded to axial compression loading similarly to those from wild-type mice (Pierroz et al, 2012). Furthermore, treatment with isoproterenol reduced cancellous and cortical bone in wild-type mice, but not in Adrb1 À /À 2 À /À mice (Pierroz et al, 2012).…”

“…Tibiae from Adrb2 À /À mice but not Adrb1 À /À mice and Adrb1 À /À 2 À /À mice responded to axial compression loading similarly to those from wild-type mice (Pierroz et al, 2012). Furthermore, treatment with isoproterenol reduced cancellous and cortical bone in wild-type mice, but not in Adrb1 À /À 2 À /À mice (Pierroz et al, 2012). Moreover, bone loss by ovariectomy similarly occurred in wildtype and Adrb1 À /À 2 À /À 3 À /À mice (Bouxsein et al, 2009).…”

“…These findings indicate that Adrb2 is responsible for the enhanced bone resorption by the sympathetic nervous system and Adrb2 is required for bone loss by estrogen depletion. Pierroz et al examined Adrb1 À /À mice, Adrb2 À /À mice, and Adrb1 À /À 2 À /À mice (Pierroz et al, 2012). Cancellous bone in vertebrae but not in femur was reduced and cortical thickness was unchanged in Adrb1 À /À mice; cancellous bone was increased in vertebrae but reduced in femurs and cortical thickness was unchanged in Adrb2 À /À mice; and cancellous bone was unchanged in both vertebrae and femurs and cortical thickness was reduced in Adrb1 À /À 2 À /À mice (Pierroz et al, 2012).…”

Extracellular Norepinephrine Clearance by the Norepinephrine Transporter Is Required for Skeletal Homeostasis

“…Ϫ/Ϫ mice were reminiscent of what had been previously observed upon pharmacological activation of ␤2AR signaling in mice or rats receiving daily ␤AR agonist injections (1,11,21). These observations suggested that lack of NET leads to overt stimulation of the ␤2AR expressed in osteoblasts, leading to bone loss.…”

The hunger games of skeletal metabolism

“…Functional b2-adrenergic receptors were identified on murine and human osteoblasts 3 and the administration of a b2-blocker to WT mice resulted in increased cancellous bone mass. 27,47 No change in cancellous bone mass was found when b2-adrenergic receptor-deficient mice were given an intracerebroventricular (i.c.v.) infusion of leptin.…”