β2-Adrenergic Receptor Signaling in Osteoblasts Contributes to the Catabolic Effect of Glucocorticoids on Bone

Abstract

The sympathetic nervous system is a physiological regulator of bone homeostasis. Autonomic nerves are indeed present in bone, bone cells express the β2-adrenergic receptors (β2AR), and pharmacological or genetic disruption of sympathetic outflow to bone induces bone gain in rodents. These recent findings implied that conditions that affect β2AR signaling in osteoblasts and/or sympathetic drive to bone may contribute to bone diseases. In this study, we show that dexamethasone stimulates the expression of the β2AR in differentiated primary calvarial osteoblasts, as measured by an increase in Adrβ2 mRNA and β2AR protein level after short-term dexamethasone treatment. Isoproterenol-induced cAMP accumulation and the expression of the β2AR target gene Rankl were also significantly increased after dexamethasone pretreatment, indicating that dexamethasone promotes the responsiveness of differentiated osteoblasts to adrenergic stimulation. These in vitro results led to the hypothesis that glucocorticoid-induced bone loss, provoked by increased endogenous or high-dose exogenous glucocorticoids given for the treatment of inflammatory diseases, might, at least in part, be mediated by increased sensitivity of bone-forming cells to the tonic inhibitory effect of sympathetic nerves on bone formation or their stimulatory effect on bone resorption. Supporting this hypothesis, both pharmacological and genetic β2AR blockade in mice significantly reduced the bone catabolic effect of high-dose prednisolone in vivo. This study emphasizes the importance of sympathetic nerves in the regulation of bone homeostasis and indicates that this neuroskeletal signaling axis can be modulated by hormones or drugs and contribute to enhance pathological bone loss.

Force-induced Adrb2 in Periodontal Ligament Cells Promotes Tooth Movement

“…Static compressive force in vitro upregulated the expression of Adrb2 in PDLCs as force was increased and force-treated time was prolonged. A previous study reported that glucocorticoids increase Adrb2 expression in osteoblasts (Ma et al, 2011). In this study, we showed that mechanical stimulation could also promote Adrb2 expression and indicated that cells in physiologic mechanical environments could be involved in the corresponding Adrb2-mediated biological responses, such as bone remodeling, through force-induced Adrb2.…”

Chronic stress, sympathetic activation and skeletal metastasis of breast cancer cells

“…In that regards, the stimulatory effect of high-dose glucocorticoids on b2AR expression in osteoblasts for instance suggests that SNS and HPA activation may synergize to favor skeletal metastasis of breast cancer cells. 64 The observation that propranolol reduced skeletal and lung establishment of breast cancer cells also suggests that bblockers could have a beneficial effect clinically in women with breast cancer. This was indeed observed in a small number of retrospective studies.…”

Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis

“…60 Evidence from mice models suggests a central regulation of bone mass by the sympathetic nervous system (SNS), mediated through leptin-regulated neural pathways. 61,62 The exact mechanisms involved in this type of regulation of bone mass, involving norepinephrine, acetylcholine, leptin, neuropeptide Y, neuromedin U, endocannabinoids, and serotonin interactions, have not been fully elucidated as yet.…”