Specific antagonists of NMDA receptors prevent osteoclast sealing zone formation required for bone resorption

N-Methyl-D-aspartate (NMDA) glutamate receptors, widely distributed in the nervous system, have recently been identified in bone. They are expressed a nd are functional in osteoclasts. In the present work, we have studied the effects of specific antagonists of NMDA receptors on osteoclast activation and bone resorption. Using an in vitro assay of bone resorption, we showed that several antagonists of NMDA receptors binding to different sites of th e receptor inhibit bone resorption. Osteoclast activation requires adhesion to the bone surface, cytoskeletal reorganization and survival. We demonstr ated by autoradiography that the specific NMDA receptor channel blocker, MK 801, binds to osteoclasts. This antagonist had no effect on osteoclast att achment to bone and did not induce osteoclast apoptosis. In contrast, MK 80 1 rapidly decreased the percentage of osteoclasts with actin ring structure s that are associated with actively resorbing osteoclasts. These results su ggest that NMDA receptors expressed by osteoclasts may be involved in adhes ion-induced formation of the sealing zone required for bone resorption. (C) 2000 Academic Press.