Glucocorticoid-induced bone loss via Beta2-adrenergic signaling in osteoblasts

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DESCRIPTION (provided by applicant): Bone remodeling, i.e. the process whereby osteoblasts and osteoclasts renew bone, is controlled by hormones, autocrine/paracrine factors and also by the central and peripheral nervous system. Indeed, we have shown that the adipocyte-derived hormone leptin inhibits bone formation via a hypothalamic relay, and that the signal between hypothalamic neurons and bones is conveyed via the sympathetic nervous system (SNS) and beta2-adrenergic receptors (?2AR) expressed in osteoblasts. In vivo, blocking of ??AR signaling increases bone formation, while stimulating ??AR signaling decreases it. Our long-term goal is to characterize the central and peripheral mechanisms whereby the nervous system controls osteoblast function. This specific application focuses on the regulation of ??AR expression in osteoblasts and its pathophysiological relevance in the context of glucocorticoid-induced bone loss. Glucocorticoids induce bone loss by a poorly characterized and still controversial mechanism of action. Our preliminary results indicate that 1) dexamethasone induces ??AR expression in osteoblasts, 2) the Adr?2 promoter contains GRE-binding sites and 3) isoproterenol, a bAR agonist, exacerbates corticosterone-induced bone loss in WT mice in vivo. In light of these results, we postulate that the mode of action of glucocorticoids requires ??AR signaling in osteoblasts and specifically that glucocorticoids increase ??AR expression and responsiveness to the SNS in osteoblasts, and thereby amplify the antiosteogenic function of the SNS, leading to bone loss. To test this hypothesis, we intend to 1) use ??AR-/- mice to test the effect of corticosterone in mice lacking ??AR signaling, 2) perform in vitro cell signaling and promoter analyses to characterize the effect of glucocorticoid treatment downstream of ??AR and on Adr?2 transcription, and 3) test in vivo the putative protective effect of b-blockers on glucocorticoid-induced bone loss. Lay summary: Glucocorticoids used for the treatment of asthma or arthritis induce bone loss by a poorly understood mechanism. We will test the hypothesis that glucocorticoids exert this action on bone by increasing bone responsiveness to neuronal signals inhibiting bone formation. Identification of such mechanism, if verified, will be an incentive for the use of beta-blockers as a preventive treatment aimed at blocking glucocorticoid-induced bone loss.