NMDA receptor in bone

A view that l-glutamic acid (Glu) plays a role as an excitatory amino acid neurotransmitter through mechanisms relevant to activities of a variety of signaling machineries essential for the neurocrine at synapses in the brain is prevailing. Although expression of functional receptors is an absolute requirement for the glutamatergic signal input in the brain, recent molecular biological and pharmacological studies including ours give rise to a novel concept for Glu as an extracellular signal mediator in the autocrine and/or paracrine system in several non-neuronal tissues outside the brain. We have demonstrated functional expression of a variety of glutamatergic signaling machineries by bone-forming osteoblasts and mechano-sensing osteocytes in bone, in addition to chondrocytes in cartilage, which are all derived from primitive mesenchymal stem cells in bone marrows. We could also detect functional expression of the cystine/Glu antiporter comprised of both xCT and 4F2hc subunits, rather than any other glutamatergic signaling machineries, by bone-resorbing osteoclasts believed to originate in hematopoietic stem cells. On the basis of these findings, we would propose a universal role of Glu as an extracellular signal mediator in the neurocrine, autocrine and paracrine systems in our body. Clinical aspect is also discussed on dietary Glu intake with a focus on possible benefits for the prophylaxis and/or treatment of osteoporosis.