| dc.description | Glutamate signalling, a major pathway of excitatory neurotransmission in the central nervous system, is proposed to be a mediator of mechanical stimulation in bone. Glutamate signalling in the central nervous system is involved in the processes of learning and memory: we postulate that glutamate receptors mediate mechanical stimulation in bone cells to increase bone density in a manner analogous to their role in mediating CNS synaptic plasticity. A variety of glutamate receptors (gluRs) of both the ionotropic and metabotropic subytpes are expressed in osteoblasts and osteoclasts of the long bones of rat, rabbit, and mouse. These receptors are sensitive to mechanical stimulation, the driving force for maintenance of normal bone density. We wished to examine the expression of glutamate receptor subtypes in cultured mouse osteoclasts and determine the effects of mechanical stimulation and estrogen on expression of these receptors. In mixed murine marrow-derived cultures, glutamate receptor antagonists MK801 and NBQX inhibited osteoclast differentiation and to some extent function, implying that these receptors are functional. NMDA receptors were colocalized with vinculin, placing them in a position where they could sense mechanical strain, receive glutamate signals from osteocytes, and be regulated by integrin-mediated activation of c-Src, which could produce transient increases in osteoclast activity to initiate bone remodeling in the absence of frequent mechanical stimulation. Frequent mechanical stimulation changed NMDA and AMPA receptor expression such that a shift in the balance of ionotropic receptor function from NMDA receptor-mediated pathways to AMPA receptor-mediated pathways occurred. Estrogen was shown to affect NMDA receptor subtype mRNA expression only in the absence of mechanical stimulation, while AMPA receptor subtype mRNA expression was affected by estrogen both in the presence and absence of mechanical stimulation. From these experiments, it is clear that glutamate signalling plays an important role in mediating osteoclast differentiation and function in response to mechanical stimulation and estrogen levels. | en_US |
