Glutamate signaling in healthy and diseased bone

Abstract

Bone relies on multiple extracellular signaling systems to maintain homeostasis of its normal structure and functions. The amino acid glutamate is a fundamental extracellular messenger molecule in many tissues, and is used in bone for both neural and non-neural signaling. This review focuses on the non-neural interactions, and examines the evolutionarily ancient glutamate signaling system in the context of its application to normal bone functioning and discusses recent findings on the role of glutamate signaling as they pertain to maintaining healthy bone structure. The underlying mechanisms of glutamate signaling and the many roles glutamate plays in modulating bone physiology are featured, including those involved in osteoclast and osteoblast differentiation and mature cell functions. Moreover, the relevance of glutamate signaling systems in diseases that affect bone, such as cancer and rheumatoid arthritis, is discussed, and will highlight how the glutamate system may be exploited as a viable therapeutic target. We will identify novel areas of research where knowledge of glutamate communication mechanisms may aid in our understanding of the complex nature of bone homeostasis. By uncovering the contributions of glutamate in maintaining healthy bone, the reader will discover how this complex molecular signaling system may advance our capacity to treat bone pathologies.

Keywords: bone; bone disease; cancer; glutamate; homeostasis; pathology; rheumatoid arthritis; signaling.

Figure 1

A summary of known glutamate receptor and transporter structures. For simplification, these structures are depicted on a generic model cell, although no cell is known to express all of these components simultaneously. Glutamate receptors are divided into either ionotropic or metabotropic types. Ionotropic receptors can incorporate different combinations of functional subunits, conferring varying response properties, and allowing for co-agonist activation. The metabotropic receptors, subdivided into three groups, are G-protein coupled membrane receptors that do not form ion channels although they can modulate other glutamate signaling components. Glutamate transporters are divided into those that are sodium-dependent and those that do not require a sodium gradient for their activity. The plasma membrane transporters (EAAT1 to EAAT5) can form ion channels and most often import glutamate. The sodium-independent transporters primarily export glutamate and these include the vesicular transporters (VGLUT-1 to VGLUT-3 and sialin) and the non-vesicular system ${\text{X}}_{\text{c}}^{–}$ glutamate/cystine antiporter.