Identification of novel signaling pathways during functional adaptation of the skeleton to mechanical loading: the role of glutamate as a paracrine signaling agent in the skeleton.

The effect of exercise on the skeleton is to initiate an adaptive response so that high levels of activity induce increased bone formation, while disuse results in bone loss. This response tunes bone mass to an appropriate level with sufficient strength but not excessive mass, which would be energetically costly to build, maintain, or use. Interest in effects of exercise on bone stems from the prevalence of diseases that feature pathological, i.e., functionally inappropriate bone loss, such as osteoporosis. If exercise regimens can be specified that maximize bone mass in early life, then even after the catastrophic loss at menopause, the bone mass of women may remain above the threshold for fracture. In addition, fuller understanding of the cascade of cellular events that follow loading of bone cells provides target processes for pharmacological mimicry of the effects of exercise in vivo. Our studies therefore address these two areas, first to identify components of loading regimens that are osteogenic and second to identify novel genes which are regulated by loading. These studies have led directly to our work identifying expression of neuronal-type glutamate receptors in bone and the intriguing possibility that intercellular communication in bone may share numerous similarities with synapses in the central nervous system.