ROLE OF GLUTAMATE IN BONE FORMATION IN VITRO

Role Of Glutamate In Bone Formation In Vitro

Role Of Glutamate In Bone Formation In Vitro

1. Introduction

Bone is an active tissue. A remodelling cycle of resorption and formation allows our skeletons to adapt to the changing physical loads we impose upon them and to self-repair. Osteoclasts and osteoblasts are the key differentiated cell types that are responsible for bone resorption and formation respectively. These cells are the progeny of resident bone marrow haematopoietic stem cells (osteoclasts) and mesenchymal stem cells (osteoblasts) and there are numerous local and systemic regulatory inputs that control the differentiation and activity of bone cells to maintain skeletal integrity. By examining the network of signalling pathways involved, we can begin to understand the fundamentals of bone biology, fracture repair, marrow stem cell activity and bone disorders such as osteoporosis. Recent attention has focused on the role of neurotransmitters and neuromodulators in bone remodelling. Initial findings generally arose from expression profiling that identified neuronal-associated genes in different bone cell populations and transgenic studies that targeted neuronal pathways and developed skeletal phenotypes. These observations suggested strongly that peripheral innervation and intrinsic neurotransmitter-like signalling in the bone microenvironment was able to influence the differentiation and activity of osteoblasts and osteoclasts and the regulation of the remodelling cycle. This review will introduce the regulatory control of bone remodelling, focusing on emerging neuro-skeletal pathways. We will concentrate on the excitatory amino acid glutamate and its contribution to the signalling hierarchy that controls bone and marrow cell behaviour. Specific attention will be given to N-methyl-d-aspartate (NMDA)-type glutamate receptor signalling mechanisms in bone. There is an accumulation of evidence to support a role for glutamate in bone biology however some reports have suggested that glutamate-like signalling does not make a significant physiological contribution. Here we will review the published data, attempt to rationalise some of the existing inconsistencies and identify potential future developments in this intriguing area of research.

2. The bone microenvironment and bone remodelling

The skeleton is a highly specialised tissue that is the developmental reward of complex embryonic patterning and post-natal/pubertal modelling processes. To maintain skeletal strength and integrity once developed old or damaged bone is periodically removed throughout life and new bone formed at local and discrete sites throughout the skeleton. This process, known as bone remodelling serves to protect skeletal function while allowing precise functional adaptation necessary to meet varying physical and metabolic demands placed upon it. In healthy individuals, remodelling occurs at an estimated 1-2 million skeletal sites (Rodan & Martin, 2000). Activity at these microscopic building sites (termed bone multi-cellular units) cumulatively accounts for the complete regeneration of the skeleton every decade and is dependent on the coordinated activities of two specialised bone cells, osteoclasts and osteoblasts resident in the bone microenvironment (Fig. 1).

Fig. 1. The bone remodelling cycle. In healthy individuals, old or damaged bone is periodically removed and new bone formed at discrete sites throughout the skeleton. This process of bone remodelling is dependent on the activities of osteoclasts and ...