Functional Glutamate Signaling in Bone

Abstract

L-glutamate (Glu) has been thought to be an excitatory amino acid neurotransmitter in the mammalian central nervous system. Relatively little attention has been paid to the functional expression of Glu signaling machineries in peripheral tissues. In this review, therefore, we summarized the possible signaling by Glu as an extracellular signal mediator in mechanisms underlying maintenance of cellular homeostasis in bone tissues. Constitutive expression of mRNAs for particular Glu receptors (GluR), Glu transporters (GluT) was found in osteoblasts. N-methyl-D-aspartic acid receptor antagonist MK-801 significantly prevented differentiation and maturation of osteoblasts through modulation of expression of Runx2. DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid significantly increased the release of endogenous Glu from osteoblasts through its receptor expressed by osteoblasts. In addition, [3H]Glu uptake was also seen in a temperature- and sodium-dependent manner with pharmacological profiles similar to those for brain GluTs in osteoblasts. Although no mRNA expression was found for all GluRs examined in primary cultured mouse osteoclasts, constitutive expression of mRNAs was seen with GluT, such as excitatory amino acid transporters and cystine/Glu antiporter. Glu markedly inhibited osteoclastogenesis in a manner sensitive to the antiporter inhibitor. The systemic administration of Glu significantly prevented the decreased bone mineral density in addition to increased osteoclastic indices in ovariectomized mice in vivo. Taken together, Glu could play a pivotal role in mechanisms underlying the maintenance of cellular homeostasis as an extracellular signal mediator in bone.