Research article Sympathetic nervous system and bone remodeling ◊ Chantal Chenu *, Massimo Marenzana Department of Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 OTU, UK Received 5 October 2005; accepted 6 October 2005 Available online 25 October 2005 Keywords: Sympathetic nervous system; Bone remodeling; Leptin; Osteoporosis 1. Introduction Adequate regulation of bone remodeling in adulthood is es- sential to maintain bone mass. In many metabolic bone dis- eases, an imbalance between bone formation and bone resorp- tion results in decreased mechanical strength. The regulation of bone remodeling was long ascribed entirely to local (autocrine and paracrine) factors and hormones. However, many recent studies suggest that bone remodeling may be controlled also by central nervous system (CNS) influences mediated by the sympathetic nervous system. The strongest piece of evidence obtained to date is the fact that leptin, a weight-controlling hormone produced by adipocytes, not only regulates the activ- ity of osteoblasts and osteoclasts by binding to a hypothalamic receptor, but also controls the release of noradrenalin by the sympathetic nervous system (SNS) [1]. This newly identified system by which the hypothalamus controls bone cell function via the autonomic nervous system may lead to exciting devel- opments in the treatment of osteoporosis. 2. Sympathetic innervation, neuromediators, and bone remodeling Histological studies have shown that the bone and perios- teum receive a rich supply of sensory and sympathetic nerve fibers. Nerve fiber density is greatest around growth plates and in the metaphyses of long bones, where they form compact parallel networks near the blood vessels adjacent to bone tra- beculae [2]. Nerve endings in direct contact with bone cells have been found, suggesting that the nerve supply may contri- bute to the regulation of bone remodeling. Catecholamine-con- taining axons have been identified near osteoblasts in vivo. Bone tissue contains large amounts of neuromediators and neu- ropeptides carried by sympathetic and sensory fibers [3]. Bone cells have functional receptors for these compounds. Osteo- blasts and osteoclasts express β-adrenoceptors, and many in vivo and in vitro studies have documented direct effects of ca- techolamines on bone cell function [4]. A number of experi- mental and clinical findings support a role for the SNS in reg- ulating bone growth and remodeling. Chemical and surgical sympathectomy experiments showed abnormal bone formation and resorption after removal of the sympathetic nerve supply [5]. Studies in genetically engineered mice established that ab- sence of receptors, transporters, and enzymes needed to pro- duce the neurotransmitters carried by sympathetic nerve fibers resulted in bone mass abnormalities (Table 1). In mice, bone mass can be decreased by giving a β-adrenoceptor agonist or increased by giving the β-blocker propranolol, confirming a role for the SNS in bone mass regulation. These experiments http://france.elsevier.com/direct/BONSOI/ Joint Bone Spine 72 (2005) 481–483 Table 1 Mutations of genes involved in SNS function leading to bone mass abnormalities Complete gene deletion Bone phenotype Receptors for neuromediators 2β-adrenoceptors High bone mass Y2R High trabecular volume Y2R (selective deletion in the hypothalamus) High trabecular volume Transporters of neuromediators Dopamine transporter Low bone mass Serotonin transporter Low bone mass Enzyme involved in catecholamine production Dopamine β-hydroxylase High bone mass * Corresponding author. E-mail address: cchenu@rvc.ac.uk (C. Chenu). ◊ Lecture held on the occasion of the 18 th French Congress for Rheumatology. 1297-319X/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2005.10.007