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Purinergic signalling in the musculoskeletal system

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Abstract

It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone-destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors.

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Acknowledgments

The authors are very grateful to Dr. Gillian E. Knight for her excellent editorial assistance during the preparation of this review article. Isabel R. Orriss and Timothy R. Arnett are very grateful to Arthritis Research UK for financial support.

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Authors and Affiliations

  1. Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK

    Geoffrey Burnstock

  2. Department of Pharmacology, The University of Melbourne, Melbourne, Australia

    Geoffrey Burnstock

  3. Department of Cell & Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK

    Timothy R. Arnett & Isabel R. Orriss

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  1. Geoffrey Burnstock
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Correspondence to Geoffrey Burnstock.

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Burnstock, G., Arnett, T.R. & Orriss, I.R. Purinergic signalling in the musculoskeletal system. Purinergic Signalling 9, 541–572 (2013). https://doi.org/10.1007/s11302-013-9381-4

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