Extracellular nucleotide signaling: A mechanism for integrating local and systemic responses in the activation of bone remodeling

Bone turnover occurs at discreet sites in the remodeling skeleton. The foca l nature of this process indicates that focal cues may facilitate the activ ation of bone cells by systemic factors. Nucleotides such as adenosine trip hosphate (ATP) are locally released, short-lived, yet potent estracelfular signaling molecules. These ligands act at a large family of receptors-the P 2 receptors, which are subdivided into P2Y and P2X subtypes based on mechan ism of signal transduction, Nucleotides enter the extracellular milieu via non-lytic and lytic mechanisms where they activate multiple P2 receptor typ es expressed by both osteoblasts and osteoclasts. In this review the releas e of ATP by bone cells is discussed in the context of activation of bone re modeling. We provide compelling evidence that nucleotides, acting via P2Y r eceptors, are potent potentiators of parathyroid hormone-induced signaling and transcriptional activation in osteoblasts. The provision of a mechanism to induce activation of osteoblasts above a threshold attained by systemic factors alone may facilitate focal remodeling and address the paradox of w hy systemic regulators like PTH exert effects at discreet sites, (C) 2001 b y Elsevier Science Inc. All rights reserved.