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.

Cancer-induced bone pain: Mechanisms and models

“…Glutamatergic transmission plays a key role in several types of pain including cancer pain [72, 19, 96]. It is also vital for normal bone homeostasis [22]. …”

Identification of capsazepine as a novel inhibitor of system x_c^− and cancer-induced bone pain

“…This secreted glutamate is believed to be a major stimulus for the initiation and propagation of CIBP following metastases to the bone. Glutamate is the most common neurotransmitter in the central nervous system, and is known to play a role in pain as well as modulating cellular homeostasis in the bone 16,17. With the nociceptive potential of glutamate implicated in a variety of painful disorders, targeting glutamate release via system x c − at the tumor site is a novel path to achieve analgesia in CIBP.…”

Monosodium Glutamate Supplementation Improves Bone Status in Mice Under Moderate Protein Restriction

“…Glutamate, as a so‐called functional amino acid, has been suggested to play a role in bone formation and mass maintenance . In addition, glutamate has been implicated in osteoblast and osteoclast differentiations . Glutamate displays a mitogenic effect on osteoblasts, and prevents decreased BMD in femur and tibia after systemic administration .…”

“…(10) In addition, glutamate has been implicated in osteoblast and osteoclast differentiations. (11,12) Glutamate displays a mitogenic effect on osteoblasts, (13) and prevents decreased BMD in femur and tibia after systemic administration. (14) A recent study also suggests that high glutamate concentration can promote differentiation and activation of osteoblasts.…”

“…(15) Moreover glutamate signaling involves both binding to specific receptors and its transport in osteoblasts. (11,(16)(17)(18) However, from in vivo experiments, it appears that virtually all the enteral glutamate in the diet is metabolized by the gut during absorption; therefore relatively large doses of glutamate in supplements have to be used to increase the glutamate concentration in portal blood, and to a lower extent in arterial blood, (19)(20)(21) which puts into question the way glutamate from dietary origin would contribute to intervene in bone physiology and metabolism.…”