[Frontiers in Bioscience S3, 1101-1118, June 1, 2011]

P2 receptor expression, signaling and function in osteoclasts

Juan P. Reyes, Stephen M. Sims, S. Jeffrey Dixon

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Osteoclast biology
2.2. P2 receptors
3. Expression, signaling and function of P2X receptors in osteoclasts
3.1. P2X2 receptors
3.2. P2X4 receptors
3.2.1. Surprising lack of Ca2+ permeability of P2X4 receptors in osteoclasts
3.3. P2X7 receptors
3.3.1. Electrophysiology
3.3.2. Permeabilization of the plasma membrane
3.3.3. Signaling
3.3.3.1. Ca2+ influx
3.3.3.2. Signaling through PKC
3.3.3.3. Signaling through NF-kB
3.3.4. Physiological roles of P2X7 receptors in osteoclasts
3.3.4.1. Role of P2X7 in the formation of multinucleated osteoclasts
3.3.4.2. Role of P2X7 in osteoblast-osteoclast and osteoclast-osteoclast communication
3.3.4.3. Role of P2X7 in regulation of the osteoclast cytoskeleton
3.3.4.4. Skeletal phenotype of P2rx7 knockout mice
3.3.4.5. P2X7 polymorphisms in humans
4. Expression, signaling and function of P2Y receptors in osteoclasts
4.1. Physiological evidence for the presence of P2Y receptors in osteoclasts
4.1.1. Ca2+ signals
4.1.2. Activation of Ca2+-dependent K+ channels
4.2. P2Y1 receptors
4.3. P2Y2 receptors
4.4. P2Y6 receptors
5. Summary and perspective
6. Acknowledgement
7. References

1. ABSTRACT

Skeletal development and bone remodeling depend on the coordinated activity of osteoblasts and osteoclasts, which are responsible for bone formation and resorption, respectively. Mature osteoclasts result from the fusion of precursor cells, and they are large, multinucleated, highly specialized cells. Cellular release of ATP and UTP occurs in response to a variety of stimuli including mechanical stimulation, which occurs in the bone environment. ATP and UTP or their metabolites can then act on P2 receptors in the plasma membrane to induce various responses in bone cells. The influence of these receptors on osteoclast physiology and bone physiology in general is beginning to be understood, but much work is still required. This review focuses on P2 receptors in osteoclasts, their expression, signaling and function in the regulation of osteoclast formation, resorptive activity and survival.