Glutamatergic regulation of bone resorption

There has been increasing evidence during the last years that glutamate (Glu), the major neuromediator of the nervous system, contributes to the local regulation of bone cell functions. Several classes of Glu receptors and transporters, as well as molecules involved in glutamate signal transduction in neuronal tissue, were identified in bone. While recent findings suggest that Glu may participate in mechanisms underlying bone formation, several studies indicate that Glu may also control bone resorption. Ionotropic NMDA and metabotropic Glu receptors are expressed by osteoclasts and electrophysiological studies have demonstrated that NMDA receptors (NMDAR) are functional on these cells. In vitro studies have shown that NMDAR are important for osteoclast function since several specific antagonists of NMDAR which block the current induced by Glu in these cells also inhibit bone resorption. Preliminary studies investigating the mechanisms of action of NMDAR antagonists on bone resorption are reviewed in this paper. There is also growing evidence that NMDAR are expressed throughout the osteoclastic differentiation sequence and that antagonists of NMDAR affect osteoclastogenesis. Very few in vivo studies have however investigated the role of Glu in skeletal metabolism and bone resorption and clearly further work is required to demonstrate the relevance of glutamate signaling in the physiology of bone resorption in vivo.