Substance P and its receptors in bone metabolism

Accumulating evidence on bone physiopathology has indicated that the skeleton contains numerous nerve fibers and its metabolism is regulated by the nervous system. Until now, more than 10 neuropeptides have been identified in bone. Substance P (SP) is a neuropeptide released from axons of sensory neurons, belongs to the tachykinin family and plays important roles in many physiological and pathological processes by acting as a neurotransmitter, neuromodulator, or trophic factor. It activates signal transduction cascades by acting on the neurokinin-1 receptor (NK(1)-R). Previous studies have confirmed that the SP-immunoreactive (IR) axons innervate bone and adjacent tissues, and that their density varies depending on the regions and physiological or pathological conditions. Over the past few decades, it has been found that SP takes part in the stimulation of bone resorption, and its receptors have been demonstrated to be located in osteoclasts. Notably, in studies of skeletal ontogeny, SP-IR axons have been shown to appear at an early stage, mostly coinciding with the sequence of long bone mineralization. These findings, together with data obtained from chemically or surgically targeted nerve deletions, strongly suggest that SP is a potent regulator of skeletal physiology. The specific distribution of SP-IR nerve fibers, the different amount of SP within regions, and the various levels of expression of NK(1)-R in targeted cells presumably related to and participate in bone metabolism. It can be predicted that the indirect roles of SP through other cytokines are as important as its direct roles in bone metabolism. This new regulating pathway of bone metabolism would have enormous implications in skeletal physiology and the relevant research might present curative potentials to a spectrum of bone diseases.