Glutamate Signaling System in Bone

Abstract

Abstract. L-Glutamate (Glu) has been thought to be an excitatory amino acid neurotransmitter in the mammalian central nervous system (CNS). The hypothesis is supported by successful cloning of a number of genes encoding different signaling molecules, such as Glu receptors for signal input, Glu transporters for signal termination, and vesicular Glu transporters for signal output through exocytotic release. Limited information is available in the literature with regard to an extracellular transmitter role of Glu in peripheral neuronal and non-neuronal tissues, whereas recent molecular biological analyses including ours give rise to a novel function for Glu as an autocrine and / or paracrine factor in bone comprised of osteoblasts, osteoclasts, and osteocytes, in addition to other peripheral tissues including pancreas, adrenal, and pituitary glands. Emerging evidence suggests that Glu could play a dual role in mechanisms underlying maintenance of cellular homeostasis as an excitatory neurotransmitter in the CNS and as an extracellular signal mediator in peripheral autocrine and / or paracrine tissues. In this review, therefore, we summarized the possible signaling by Glu as an extracellular signal mediator in mechanisms underlying maintenance of cellular homeostasis with a focus on bone tissues.

Cancer cell lines release glutamate into the extracellular environment

“…Many intercellular signalling mechanisms have been reviewed in this context, and when disrupted, their altered functioning may account for some of the pathological responses to tumour cell invasion [5][6][7]. An intracellular communication system critical to bone homeostasis that has received considerable attention recently employs the amino acid L-glutamate as a chemical signalling molecule [6,8,9]. L-glutamate, being both a metabolic fuel and building block for protein synthesis, is also the predominant excitatory neurotransmitter in the central nervous system (CNS) [10,11].…”

“…Although the mechanics of glutamatergic signalling were characterized primarily in the CNS, the importance of glutamate signalling in non-neuronal tissues is becoming more recognized in the literature [12,13]. Glutamate is used extensively by normal bone cells for a variety of homeostatic functions [8,9,[14][15][16][17][18][19], with specific glutamate receptors and transporters expressed in osteoblasts [18,[20][21][22][23][24], osteoclasts [18,20,21], and osteocytes [18,25]. As an organ system, bone maintains its balanced metabolic state using a combination of paracrine factors, short range chemical signals (including glutamate), and direct cell-to-cell communication [26].…”

Hyaluronic acid attenuates osteoarthritis development in the anterior cruciate ligament‐transected knee: Association with excitatory amino acid release in the joint dialysate

“…43,44 Furthermore, glutamate was demonstrated to mediate intercellular communication in bone cells, in a manner similar to the synaptic transmission in the CNS, it contributes to bone matrix regulation. 45,46 Consititutive release of glutamate was demonstrated in cultured calvarial rat osteoblasts via a voltage-dependent calcium entry mechanism. 43 The expression of NMDA receptors in human and rat osteoblasts and osteoclasts suggests a role of glutamate in bone cells signalling.…”

A glycine ruthenium trithiacyclononane complex and its molecular encapsulation using cyclodextrins

“…Osteoblasts express glutamate receptors, in which glycine acts as a co-agonist, 17 and have thus been proposed as suitable targets for osteosarcoma chemotherapy by using compounds able to bind and block the receptors, inhibiting normal osteoblast functionality. 18 We therefore chose to incorporate the amino acid glycine, designing the ruthenium complex for glutamate receptor specific binding and subsequent blockage by the Ru-trithiacyclononane cap.…”