[Frontiers in Bioscience 16, 2572-2585, June 1, 2011]

Role of purinergic receptor polymorphisms in human bone

Anke Wesselius1, Martijn J.L. Bours1, Ankita Agrawal2, Alison Gartland2, Pieter C. Dagnelie1, Peter Schwarz3,4, Niklas R. Jorgensen3

1University of Maastricht, Department of Epidemiology, School for Public Health and Primary Care (CAPHRI) , P.O. Box 616, 6200 MD, Maastricht, The Netherlands, 2The Mellanby Centre for Bone Research, Dept. Human Metabolism, The University of Sheffield, S10 2RX, UK, 3University Hospital of Copenhagen Glostrup , Research Center for Ageing and Osteoporosis and Dept. of Clinical Chemistry, Glostrup, Ndr Ringvej 57-59, DK-2600 Glostrup, Denmark, 4Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. ATP and purinergic signalling in bone
3.1. Effects of ATP and purinergic P2 receptors on osteoclast function
3.2. Effects of ATP and purinergic P2 receptors on osteoblast function
3.3. Role of ATP and purinergic P2 receptors in mechanotransduction
3.4. The interaction of purinergic signalling with systemic factors
4. Single nucleotide polymorphisms in osteoporosis
4.1. Functional P2X7 receptor SNPs
4.2. Effect of combined genotypes and haplotypes in the P2X7 receptor gene
4.3. Role of P2X7 receptor SNPs in osteoporosis
4.4. Role of P2X7 receptor SNPs in other human diseases
4.5. Functional P2Y2 receptor SNPs
4.6. Role of P2Y2 receptor SNPs in osteoporosis
4.7. Role of P2Y2 receptor SNPs in other human diseases
5. Perspective
6. Conclusion
7. Acknowledgements
8. References

1. ABSTRACT

Osteoporosis is a multifactorial disease with a strong genetic component. Variations in a number of genes have been shown to associate with bone turnover and risk of osteoporosis. P2 purinergic receptors are proteins that have ATP or other nucleotides as their natural ligands. Various P2Y and P2X receptor subtypes have been identified on bone cells. Several cellular functions in bone tissue are coupled to P2-receptor activation, including bone resorption, cytokine release, apoptosis, bone formation, and mineral deposition. Furthermore, ATP release and P2 purinergic signalling is a key pathway in the mechanotransductory process, where mechanical stimulation on bone leads to anabolic responses in the skeleton. A number of single nucleotide polymorphisms have been identified in the P2 receptor genes, where especially the P2X7 subtype has been the focus of extensive investigation where several polymorphisms have been shown to have functional implications on receptor function; moreover, some polymorphisms are associated with alterations in bone turnover and bone mass. This review focuses on variations in P2 receptor genes and the association to bone turnover and -quality.