Purinergic Signalling

, Volume 9, Issue 4, pp 541–572 | Cite as

Purinergic signalling in the musculoskeletal system

  • Geoffrey Burnstock
  • Timothy R. Arnett
  • Isabel R. Orriss
Review Article


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.


Bone Cartilage Joints Arthritis Muscular dystrophy Cancer 



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.


  1. 1.
    Buchthal F, Folkow B (1944) Close arterial injection of adenosine triphosphate and inorganic triphosphate into frog muscle. Acta Physiol Scand 8:312–316Google Scholar
  2. 2.
    Buchthal F, Folkow B (1948) Interaction between acetylcholine and adenosine triphosphate in normal, curarised and denervated muscle. Acta Physiol Scand 15:150–160PubMedGoogle Scholar
  3. 3.
    Dowdall MJ, Boyne AF, Whittaker VP (1974) Adenosine triphosphate. A constituent of cholinergic synaptic vesicles. Biochem J 140:1–12PubMedPubMedCentralGoogle Scholar
  4. 4.
    Zimmermann H (1982) Co-existence of adenosine 5′-triphosphate and acetylcholine in the electromotor synapse. In: Cuello AC (ed) Co-transmission. Macmillan, London, pp 243–259Google Scholar
  5. 5.
    Silinsky EM, Hubbard JI (1973) Release of ATP from rat motor nerve terminals. Nature 243:404–405PubMedGoogle Scholar
  6. 6.
    Silinsky EM (1975) On the association between transmitter secretion and the release of adenine nucleotides from mammalian motor nerve terminals. J Physiol 247:145–162PubMedPubMedCentralGoogle Scholar
  7. 7.
    Kumagai H, Sakamoto H, Guggino S, Filburn CR, Sacktor B (1989) Neurotransmitter regulation of cytosolic calcium in osteoblast-like bone cells. Calcif Tissue Int 45:251–254PubMedGoogle Scholar
  8. 8.
    Kumagai H, Sacktor B, Filburn CR (1991) Purinergic regulation of cytosolic calcium and phosphoinositide metabolism in rat osteoblast-like osteosarcoma cells. J Bone Miner Res 6:697–708PubMedGoogle Scholar
  9. 9.
    Reimer WJ, Dixon SJ (1992) Extracellular nucleotides elevate [Ca2+]i in rat osteoblastic cells by interaction with two receptor subtypes. Am J Physiol 263:C1040–C1048PubMedGoogle Scholar
  10. 10.
    Yu H, Ferrier J (1993) ATP induces an intracellular calcium pulse in osteoclasts. Biochem Biophys Res Commun 191:357–363PubMedGoogle Scholar
  11. 11.
    Hoebertz A, Mahendran S, Burnstock G, Arnett TR (2002) ATP and UTP at low concentrations strongly inhibit bone formation by osteoblasts: a novel role for the P2Y2 receptor in bone remodelling. Journal of Cellular Biochemistry 86:413–419PubMedGoogle Scholar
  12. 12.
    Morrison MS, Turin L, King BF, Burnstock G, Arnett TR (1998) ATP is a potent stimulator of the activation and formation of rodent osteoclasts. J Physiol 511:495–500PubMedPubMedCentralGoogle Scholar
  13. 13.
    Burnstock G, Verkhratsky A (2012) Purinergic signalling and the nervous system. Springer, Heidelberg, pp 1–715Google Scholar
  14. 14.
    Wells DG, Zawisa MJ, Hume RI (1995) Changes in responsiveness to extracellular ATP in chick skeletal muscle during development and upon denervation. Dev Biol 172:585–590PubMedGoogle Scholar
  15. 15.
    Silinsky EM, Redman RS (1996) Synchronous release of ATP and neurotransmitter within milliseconds of a motor nerve impulse in the frog. J Physiol 492:815–822PubMedPubMedCentralGoogle Scholar
  16. 16.
    Sokolova E, Grishin S, Shakirzyanova A, Talantova M, Giniatullin R (2003) Distinct receptors and different transduction mechanisms for ATP and adenosine at the frog motor nerve endings. Eur J Neurosci 18:1254–1264PubMedGoogle Scholar
  17. 17.
    Tung EK, Choi RC, Siow NL, Jiang JX, Ling KK, Simon J, Barnard EA, Tsim KW (2004) P2Y2 receptor activation regulates the expression of acetylcholinesterase and acetylcholine receptor genes at vertebrate neuromuscular junctions. Mol Pharmacol 66:794–806PubMedGoogle Scholar
  18. 18.
    Giniatullin AR, Grishin SN, Sharifullina ER, Petrov AM, Zefirov AL, Giniatullin RA (2005) Reactive oxygen species contribute to the presynaptic action of extracellular ATP at the frog neuromuscular junction. J Physiol 565:229–242PubMedPubMedCentralGoogle Scholar
  19. 19.
    Grishin S, Shakirzyanova A, Giniatullin A, Afzalov R, Giniatullin R (2005) Mechanisms of ATP action on motor nerve terminals at the frog neuromuscular junction. Eur J Neurosci 21:1271–1279PubMedGoogle Scholar
  20. 20.
    Ahdut-Hacohen R, Meiri H, Rahamimoff R (2006) ATP dependence of the non-specific ion channel in Torpedo synaptic vesicles. Neuroreport 17:653–656PubMedGoogle Scholar
  21. 21.
    Massé K, Eason R, Bhamra S, Dale N, Jones EA (2006) Comparative genomic and expression analysis of the conserved NTPDase gene family in Xenopus. Genomics 87:366–381PubMedGoogle Scholar
  22. 22.
    Ginsborg BL, Hirst GDS (1972) The effect of adenosine on the release of the transmitter from the phrenic nerve of the rat. J Physiol 224:629–645PubMedPubMedCentralGoogle Scholar
  23. 23.
    Ribeiro JA, Walker J (1975) The effects of adenosine triphosphate and adenosine diphosphate on transmission at the rat and frog neuromuscular junctions. Br J Pharmacol 54:213–218PubMedPubMedCentralGoogle Scholar
  24. 24.
    Silinsky EM (1984) On the mechanism by which adenosine receptor activation inhibits the release of acetylcholine from motor nerve endings. J Physiol 346:243–256PubMedPubMedCentralGoogle Scholar
  25. 25.
    Silinsky EM (2008) Selective disruption of the mammalian secretory apparatus enhances or eliminates calcium current modulation in nerve endings. Proc Natl Acad Sci U S A 105:6427–6432PubMedPubMedCentralGoogle Scholar
  26. 26.
    Ribeiro JA, Sebastiao AM (1987) On the role, inactivation and origin of endogenous adenosine at the frog neuromuscular junction. J Physiol 384:571–585PubMedPubMedCentralGoogle Scholar
  27. 27.
    Smith DO (1991) Sources of adenosine released during neuromuscular transmission in the rat. J Physiol 432:343–354PubMedPubMedCentralGoogle Scholar
  28. 28.
    Barroso A, Oliveira L, Campesatto-Mella E, Silva C, Timóteo MA, Magãlhaes-Cardoso MT, Alves-do-Prado W, Correia-de-Sá P (2007) L-citrulline inhibits [3H]acetylcholine release from rat motor nerve terminals by increasing adenosine outflow and activation of A1 receptors. Br J Pharmacol 151:541–550PubMedPubMedCentralGoogle Scholar
  29. 29.
    Ribeiro JA (1977) Potentiation of postjunctional cholinergic sensitivity of rat diaphragm muscle by high-energy-phosphate adenine nucleotides. J Membr Biol 33:401–402PubMedGoogle Scholar
  30. 30.
    Kolb HA, Wakelam MJO (1983) Transmitter-like action of ATP on patched membranes of cultured myoblasts and myotubes. Nature 303:621–623PubMedGoogle Scholar
  31. 31.
    Lu Z, Smith DO (1991) Adenosine 5′-triphosphate increases acetylcholine channel opening frequency in rat skeletal muscle. J Physiol 436:45–56PubMedPubMedCentralGoogle Scholar
  32. 32.
    Henning RH (1997) Purinoceptors in neuromuscular transmission. Pharmacol Ther 74:115–128PubMedGoogle Scholar
  33. 33.
    Heilbronn E, Eriksson H (1998) Second messengers mobilized by ATP and ACh in the myotube/muscle fiber. In: Sellin LC, Libelius R, Thesleff S (eds) Neuromuscular junction. Elsevier, Amsterdam, pp 395–404Google Scholar
  34. 34.
    Silinsky EM, Hirsh JK, Searl TJ, Redman RS, Watanabe M (1999) Quantal ATP release from motor nerve endings and its role in neurally mediated depression. Prog Brain Res 120:145–158PubMedGoogle Scholar
  35. 35.
    Dowdall MJ (1975) Synthesis and storage of acetylcholine in cholinergic nerve terminals. In: Berl S, Clarke DD, Schneider D (eds) Metabolic compartmentation and neurotransmission. Plenum, New York, pp 585–607Google Scholar
  36. 36.
    Schweitzer E (1987) Coordinated release of ATP and ACh from cholinergic synaptosomes and its inhibition by calmodulin antagonists. J Neurosci 7:2948–2956PubMedGoogle Scholar
  37. 37.
    Correia-de-Sá P, Timóteo MA, Ribeiro JA (1996) Presynaptic A1 inhibitory/A2A facilitatory adenosine receptor activation balance depends on motor nerve stimulation paradigm at the rat hemidiaphragm. J Neurophysiol 76:3910–3919PubMedGoogle Scholar
  38. 38.
    Pousinha PA, Correia AM, Sebastião AM, Ribeiro JA (2010) Predominance of adenosine excitatory over inhibitory effects on transmission at the neuromuscular junction of infant rats. J Pharmacol Exp Ther 332:153–163PubMedGoogle Scholar
  39. 39.
    Salgado AI, Cunha RA, Ribeiro JA (2000) Facilitation by P2 receptor activation of acetylcholine release from rat motor nerve terminals: interaction with presynaptic nicotinic receptors. Brain Res 877:245–250PubMedGoogle Scholar
  40. 40.
    Garcia N, Priego M, Obis T, Santafe MM, Tomàs M, Besalduch N, Lanuza MA, Tomàs J (2013) Adenosine A1 and A2A receptor-mediated modulation of acetylcholine release in the mice neuromuscular junction. Eur J Neurosci Epub ahead of printGoogle Scholar
  41. 41.
    Moores TS, Hasdemir B, Vega-Riveroll L, Deuchars J, Parson SH (2005) Properties of presynaptic P2X7-like receptors at the neuromuscular junction. Brain Res 1034:40–50PubMedGoogle Scholar
  42. 42.
    Parson SH, Iqbal R (2000) Mouse motor nerve terminals release synaptic vesicles following activation of P2X7 receptors. J Physiol 528:60PGoogle Scholar
  43. 43.
    Galkin AV, Giniatullin RA, Mukhtarov MR, Svandova I, Grishin SN, Vyskocil F (2001) ATP but not adenosine inhibits nonquantal acetylcholine release at the mouse neuromuscular junction. Eur J Neurosci 13:2047–2053PubMedGoogle Scholar
  44. 44.
    De Lorenzo S, Veggetti M, Muchnik S, Losavio A (2006) Presynaptic inhibition of spontaneous acetylcholine release mediated by P2Y receptors at the mouse neuromuscular junction. Neuroscience 142:71–85PubMedGoogle Scholar
  45. 45.
    Veggetti M, Muchnik S, Losavio A (2008) Effect of purines on calcium-independent acetylcholine release at the mouse neuromuscular junction. Neuroscience 154:1324–1336PubMedGoogle Scholar
  46. 46.
    Malomouzh AI, Nikolsky EE, Vyskocil F (2011) Purine P2Y receptors in ATP-mediated regulation of non-quantal acetylcholine release from motor nerve endings of rat diaphragm. Neurosci Res 71:219–225PubMedGoogle Scholar
  47. 47.
    Su TR, Hung YS, Huang SS, Su HH, Su CC, Hsiao G, Chen YH, Lin MJ (2011) Study of the reversal effect of NF449 on neuromuscular blockade induced by d-tubocurarine. Life Sci 88:1039–1046PubMedGoogle Scholar
  48. 48.
    Naumenko NV, Uzinskaya KV, Shakirzyanova AV, Urazaev AK, Zefirov AL (2009) Adenosine triphosphoric acid as a factor of nervous regulation of Na+/K+/2Cl- cotransport in rat skeletal muscle fibers. Bull Exp Biol Med 147:583–586PubMedGoogle Scholar
  49. 49.
    Ryten M, Hoebertz A, Burnstock G (2001) Sequential expression of three receptor subtypes for extracellular ATP in developing rat skeletal muscle. Dev Dyn 221:331–341PubMedGoogle Scholar
  50. 50.
    Khakh BS, Zhou X, Sydes J, Galligan JJ, Lester HA (2000) State-dependent cross-inhibition between transmitter-gated cation channels. Nature 406:405–410PubMedGoogle Scholar
  51. 51.
    Ryten M, Koshi R, Knight GE, Turmaine M, Dunn PM, Cockayne DA, Ford APDW, Burnstock G (2007) Abnormalities in neuromuscular junction structure and skeletal muscle function in mice lacking the P2X2 nucleotide receptor. Neuroscience 148:700–711PubMedGoogle Scholar
  52. 52.
    Jia M, Li MX, Fields RD, Nelson PG (2007) Extracellular ATP in activity-dependent remodeling of the neuromuscular junction. Dev Neurobiol 67:924–932PubMedGoogle Scholar
  53. 53.
    Light AR, Hughen RW, Zhang J, Rainier J, Liu Z, Lee J (2008) Dorsal root ganglion neurons innervating skeletal muscle respond to physiological combinations of protons, ATP, and lactate mediated by ASIC, P2X, and TRPV1. J Neurophysiol 100:1184–1201PubMedGoogle Scholar
  54. 54.
    McCord JL, Tsuchimochi H, Kaufman MP (2010) P2X2/3 and P2X3 receptors contribute to the metaboreceptor component of the exercise pressor reflex. J Appl Physiol 109:1416–1423PubMedPubMedCentralGoogle Scholar
  55. 55.
    Schoenberg M (1989) Effect of adenosine triphosphate analogues on skeletal muscle fibers in rigor. Biophys J 56:33–41PubMedPubMedCentralGoogle Scholar
  56. 56.
    Buvinic S, Almarza G, Bustamante M, Casas M, López J, Riquelme M, Sáez JC, Huidobro-Toro JP, Jaimovich E (2009) ATP released by electrical stimuli elicits calcium transients and gene expression in skeletal muscle. J Biol Chem 284:34490–34505PubMedPubMedCentralGoogle Scholar
  57. 57.
    Mortensen SP, González-Alonso J, Nielsen JJ, Saltin B, Hellsten Y (2009) Muscle interstitial ATP and norepinephrine concentrations in the human leg during exercise and ATP infusion. J Appl Physiol 107:1757–1762PubMedGoogle Scholar
  58. 58.
    Tu J, Lu L, Cai W, Ballard HJ (2012) cAMP/protein kinase A activates cystic fibrosis transmembrane conductance regulator for ATP release from rat skeletal muscle during low pH or contractions. PLoS One 7:e50157PubMedPubMedCentralGoogle Scholar
  59. 59.
    Keresztes M, Häggblad J, Heilbronn E (1991) Basal and ATP-stimulated phosphoinositol metabolism in fusing rat skeletal muscle cells in culture. Exp Cell Res 196:362–364PubMedGoogle Scholar
  60. 60.
    Allard B, Lazdunski M (1992) Nucleotide diphosphates activate the ATP-sensitive potassium channel in mouse skeletal muscle. Pflugers Arch 422:185–192PubMedGoogle Scholar
  61. 61.
    Ayyanathan K, Webbs TE, Sandhu AK, Athwal RS, Barnard EA, Kunapuli SP (1996) Cloning and chromosomal localization of the human P2Y1 purinoceptor. Biochem Biophys Res Commun 218:783–788PubMedGoogle Scholar
  62. 62.
    Urano T, Nishimori H, Han H, Furuhata T, Kimura Y, Nakamura Y, Tokino T (1997) Cloning of P2XM, a novel human P2X receptor gene regulated by p53. Cancer Res 57:3281–3287PubMedGoogle Scholar
  63. 63.
    Bo X, Schoepfer R, Burnstock G (2000) Molecular cloning and characterization of a novel ATP P2X receptor subtype from embryonic chick skeletal muscle. J Biol Chem 275:14401–14407PubMedGoogle Scholar
  64. 64.
    Ruppelt A, Liang BT, Soto F (1999) Cloning, functional characterization and developmental expression of a P2X receptor from chick embryo. Prog Brain Res 120:81–90PubMedGoogle Scholar
  65. 65.
    Ruppelt A, Ma W, Borchardt K, Silberberg SD, Soto F (2001) Genomic structure, developmental distribution and functional properties of the chicken P2X5 receptor. J Neurochem 77:1256–1265PubMedGoogle Scholar
  66. 66.
    Csernoch L, Cseri J, Mallouk N, Kovács L (2000) ATP-induced changes of intracellular calcium concentration in human skeletal muscle fibres in culture. J Physiol 526:30P–31PGoogle Scholar
  67. 67.
    Meyer MP, Gröschel-Stewart U, Robson T, Burnstock G (1999) Expression of two ATP-gated ion channels, P2X5 and P2X6, in developing chick skeletal muscle. Dev Dyn 216:442–449PubMedGoogle Scholar
  68. 68.
    Soto F, Krause U, Borchardt K, Ruppelt A (2003) Cloning, tissue distribution and functional characterization of the chicken P2X1 receptor. FEBS Lett 533:54–58PubMedGoogle Scholar
  69. 69.
    Sandona D, Danieli-Betto D, Germinario E, Biral D, Martinello T, Lioy A, Tarricone E, Gastaldello S, Betto R (2005) The T-tubule membrane ATP-operated P2X4 receptor influences contractility of skeletal muscle. FASEB J 19:1184–1186PubMedGoogle Scholar
  70. 70.
    Banachewicz W, Suplat D, Krzeminski P, Pomorski P, Baranska J (2005) P2 nucleotide receptors on C2C12 satellite cells. Purinergic Signal 1:249–257PubMedPubMedCentralGoogle Scholar
  71. 71.
    Rassendren F, Buell GN, Virginio C, Collo G, North RA, Surprenant A (1997) The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA. J Biol Chem 272:5482–5486PubMedGoogle Scholar
  72. 72.
    Ryten M, Dunn PM, Neary JT, Burnstock G (2002) ATP regulates the differentiation of mammalian skeletal muscle by activation of a P2X 5 receptor on satellite cells. J Cell Biol 158:345–355PubMedPubMedCentralGoogle Scholar
  73. 73.
    Deli T, Szappanos H, Szigeti GP, Cseri J, Kovacs L, Csernoch L (2007) Contribution from P2X and P2Y purinoreceptors to ATP-evoked changes in intracellular calcium concentration on cultured myotubes. Pflugers Arch 453:519–529PubMedGoogle Scholar
  74. 74.
    Henning RH, Duin M, Den Hertog A, Nelemans A (1993) Characterization of P2-purinoceptor mediated cyclic AMP formation in mouse C2C12 myotubes. Br J Pharmacol 110:133–138PubMedPubMedCentralGoogle Scholar
  75. 75.
    Cheung K-K, Ryten M, Burnstock G (2003) Abundant and dynamic expression of G protein-coupled P2Y receptors in mammalian development. Dev Dyn 228:254–266PubMedGoogle Scholar
  76. 76.
    Parr CE, Sullivan DM, Paradiso AM, Lazarowski ER, Burch LH, Olsen JC, Erb L, Weisman GA, Boucher RC, Turner JT (1994) Cloning and expression of a human P2U nucleotide receptor, a target for cystic fibrosis pharmacotherapy. Proc Natl Acad Sci USA 91:3275–3279PubMedPubMedCentralGoogle Scholar
  77. 77.
    Janssens R, Communi D, Pirotton S, Samson M, Parmentier M, Boeynaems JM (1996) Cloning and tissue distribution of the human P2Y1 receptor. Biochem Biophys Res Commun 221:588–593PubMedGoogle Scholar
  78. 78.
    Cseri J, Szappanos H, Szigeti GP, Csernatony Z, Kovacs L, Csernoch L (2002) A purinergic signal transduction pathway in mammalian skeletal muscle cells in culture. Pflugers Arch 443:731–738PubMedGoogle Scholar
  79. 79.
    Pietrangelo T, Fioretti B, Mancinelli R, Catacuzzeno L, Franciolini F, Fanò G, Fulle S (2006) Extracellular guanosine-5'-triphosphate modulates myogenesis via intermediate Ca2+-activated K+ currents in C2C12 mouse cells. J Physiol 572:721–733PubMedPubMedCentralGoogle Scholar
  80. 80.
    Araya R, Riquelme MA, Brandan E, Sáez JC (2004) The formation of skeletal muscle myotubes requires functional membrane receptors activated by extracellular ATP. Brain Res Brain Res Rev 47:174–188PubMedGoogle Scholar
  81. 81.
    Teplov AY, Grishin SN, Zefirov AL, Ziganshin AU (2006) Role of protein kinase C in the effect of ATP on contractile function of the isolated strip from mouse diaphragm. Bull Exp Biol Med 141:407–409PubMedGoogle Scholar
  82. 82.
    Deli T, Tóth BI, Czifra G, Szappanos H, Bíró T, Csernoch L (2006) Differences in purinergic and voltage-dependent signalling during protein kinase Cα overexpression- and culturing-induced differentiation of C2C12 myoblasts. J Muscle Res Cell Motil 27:617–630PubMedGoogle Scholar
  83. 83.
    Stiber JA, Tabatabaei N, Hawkins AF, Hawke T, Worley PF, Williams RS, Rosenberg P (2005) Homer modulates NFAT-dependent signaling during muscle differentiation. Dev Biol 287:213–224PubMedGoogle Scholar
  84. 84.
    Blaauw B, Del Piccolo P, Rodriguez L, Gonzalez VHH, Agatea L, Solagna F, Mammano F, Pozzan T, Schiaffino S (2012) No evidence for inositol 1,4,5-trisphosphate-dependent Ca2+ release in isolated fibers of adult mouse skeletal muscle. J Gen Physiol 140:235–241PubMedPubMedCentralGoogle Scholar
  85. 85.
    May C, Weigl L, Karel A, Hohenegger M (2006) Extracellular ATP activates ERK1/ERK2 via a metabotropic P2Y1 receptor in a Ca2+ independent manner in differentiated human skeletal muscle cells. Biochem Pharmacol 71:1497–1509PubMedGoogle Scholar
  86. 86.
    Choi RC, Siow NL, Cheng AW, Ling KK, Tung EK, Simon J, Barnard EA, Tsim KW (2003) ATP acts via P2Y1 receptors to stimulate acetylcholinesterase and acetylcholine receptor expression: transduction and transcription control. J Neurosci 23:4445–4456PubMedGoogle Scholar
  87. 87.
    Voss AA (2009) Extracellular ATP inhibits chloride channels in mature mammalian skeletal muscle by activating P2Y1 receptors. J Physiol 587:5739–5752PubMedPubMedCentralGoogle Scholar
  88. 88.
    Walas H, Juel C (2012) Purinergic activation of rat skeletal muscle membranes increases Vmax and Na + affinity of the Na, K-ATPase and phosphorylates phospholemman and α1 subunits. Pflugers Arch 463:319–326PubMedGoogle Scholar
  89. 89.
    Broch-Lips M, Pedersen TH, Nielsen OB (2010) Effect of purinergic receptor activation on Na+-K+ pump activity, excitability, and function in depolarized skeletal muscle. Am J Physiol Cell Physiol 298:C1438–C1444PubMedGoogle Scholar
  90. 90.
    Rathmacher JA, Fuller JC Jr, Baier SM, Abumrad NN, Angus HF, Sharp RL (2012) Adenosine-5'-triphosphate (ATP) supplementation improves low peak muscle torque and torque fatigue during repeated high intensity exercise sets. J Int Soc Sports Nutr 9:48PubMedPubMedCentralGoogle Scholar
  91. 91.
    Germinario E, Esposito A, Midrio M, Peron S, Palade PT, Betto R, Danieli-Betto D (2008) High-frequency fatigue of skeletal muscle: role of extracellular Ca2+. Eur J Appl Physiol 104:445–453PubMedPubMedCentralGoogle Scholar
  92. 92.
    Cea LA, Riquelme MA, Cisterna BA, Puebla C, Vega JL, Rovegno M, Sáez JC (2012) Connexin- and pannexin-based channels in normal skeletal muscles and their possible role in muscle atrophy. J Membr Biol 245:423–436PubMedGoogle Scholar
  93. 93.
    Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, Espinosa A, Li Q, Niu W, Lavandero S, Klip A, Jaimovich E (2013) Electrical stimuli release ATP to increase GLUT4 translocation and glucose uptake via PI3Kγ-Akt-AS160 in skeletal muscle cells. Diabetes 62:1519–1526PubMedGoogle Scholar
  94. 94.
    Jaimovich E, Bustamante M, Fernández R, Buvinic S (2011) ATP released by electrical stimulation of myotubes triggers IL6 expression and increases STAT3 activity. FASEB J 25:1105.20Google Scholar
  95. 95.
    Taguchi T, Kozaki Y, Katanosaka K, Mizumura K (2008) Compression-induced ATP release from rat skeletal muscle with and without lengthening contraction. Neurosci Lett 434:277–281PubMedGoogle Scholar
  96. 96.
    Martinello T, Baldoin MC, Morbiato L, Paganin M, Tarricone E, Schiavo G, Bianchini E, Sandona D, Betto R (2011) Extracellular ATP signaling during differentiation of C2C12 skeletal muscle cells: role in proliferation. Mol Cell Biochem 351:183–196PubMedGoogle Scholar
  97. 97.
    Sciancalepore M, Luin E, Parato G, Ren E, Giniatullin R, Fabbretti E, Lorenzon P (2012) Reactive oxygen species contribute to the promotion of the ATP-mediated proliferation of mouse skeletal myoblasts. Free Radic Biol Med 53:1392–1398PubMedGoogle Scholar
  98. 98.
    Li J, Sinoway LI (2002) ATP stimulates chemically sensitive and sensitizes mechanically sensitive afferents. Am J Physiol Heart Circ Physiol 283:H2636–H2643PubMedGoogle Scholar
  99. 99.
    Li J, King NC, Sinoway LI (2003) ATP concentrations and muscle tension increase linearly with muscle contraction. J Appl Physiol 95:577–583PubMedGoogle Scholar
  100. 100.
    Laver DR, Lenz GK, Lamb GD (2001) Regulation of the calcium release channel from rabbit skeletal muscle by the nucleotides ATP, AMP, IMP and adenosine. J Physiol 537:763–778PubMedPubMedCentralGoogle Scholar
  101. 101.
    Wolner I, Kassack MU, Ullmann H, Karel A, Hohenegger M (2005) Use-dependent inhibition of the skeletal muscle ryanodine receptor by the suramin analogue NF676. Br J Pharmacol 146:525–533PubMedPubMedCentralGoogle Scholar
  102. 102.
    Dias JM, Vogel PD (2009) Effects of small molecule modulators on ATP binding to skeletal ryanodine receptor. Protein J 28:240–246PubMedGoogle Scholar
  103. 103.
    Szigeti GP, Szappanos H, Deli T, Cseri J, Kovács L, Csernoch L (2007) Differentiation-dependent alterations in the extracellular ATP-evoked calcium fluxes of cultured skeletal muscle cells from mice. Pflugers Arch 453:509–518PubMedGoogle Scholar
  104. 104.
    Choo HJ, Kim BW, Kwon OB, Lee CS, Choi JS, Ko YG (2008) Secretion of adenylate kinase 1 is required for extracellular ATP synthesis in C2C12 myotubes. Exp Mol Med 40:220–228PubMedPubMedCentralGoogle Scholar
  105. 105.
    Rigault C, Bernard A, Georges B, Kandel A, Pfützner E, Le Borgne F, Demarquoy J (2008) Extracellular ATP increases L-carnitine transport and content in C2C12 cells. Pharmacology 81:246–250PubMedGoogle Scholar
  106. 106.
    Warren GL, Hulderman T, Liston A, Simeonova PP (2011) Toll-like and adenosine receptor expression in injured skeletal muscle. Muscle Nerve 44:85–92PubMedGoogle Scholar
  107. 107.
    Urso ML, Wang R, Zambraski EJ, Liang BT (2012) Adenosine A3 receptor stimulation reduces muscle injury following physical trauma and is associated with alterations in the MMP/TIMP response. J Appl Physiol 112:658–670PubMedGoogle Scholar
  108. 108.
    Bradbeer JN, Gowen M, Dodds RA (1992) In situ demonstration of the increased ability of human osteoclasts to generate ATP during bone resorption. J Bone Miner Res 7:S312Google Scholar
  109. 109.
    Schöfl C, Cuthbertson KS, Walsh CA, Mayne C, Cobbold P, von zur Muhlen A, Hesch RD, Gallagher JA (1992) Evidence for P2-purinoceptors on human osteoblast-like cells. J Bone Miner Res 7:485–491PubMedGoogle Scholar
  110. 110.
    Orriss IR, Burnstock G, Arnett TR (2010) Purinergic signalling and bone remodelling. Curr Opin Pharmacol 10:322–330PubMedGoogle Scholar
  111. 111.
    Orriss IR, Arnett TR (2012) P2Y receptors in bone. WIREs Membr Transp Signal 1:805–814Google Scholar
  112. 112.
    Gartland A (2012) P2X receptors in bone. WIREs Membr Transp Signal 1:221–227Google Scholar
  113. 113.
    Gartland A, Orriss IR, Rumney RM, Bond AP, Arnett T, Gallagher JA (2012) Purinergic signalling in osteoblasts. Front Biosci 17:16–29Google Scholar
  114. 114.
    Gartland A, Buckley KA, Hipskind RA, Perry MJ, Tobias JH, Buell G, Chessell I, Bowler WB, Gallagher JA (2003) Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice. Crit Rev Eukaryot Gene Expr 13:243–253PubMedGoogle Scholar
  115. 115.
    Ke HZ (2005) In vivo characterization of skeletal phenotype of genetically modified mice. J Bone Miner Metab 23(Suppl):84–89PubMedGoogle Scholar
  116. 116.
    Steinberg TH, Hiken JF (2007) P2 receptors in macrophage fusion and osteoclast formation. Purinergic Signal 3:53–57PubMedPubMedCentralGoogle Scholar
  117. 117.
    Orriss I, Evans H, Arnett T, Gartland A (2008) MicroCT analysis of P2Y1 and P2Y2 receptor knockout mice demonstrates significant changes in bone phenotype. Purinergic Signal 4:1–210Google Scholar
  118. 118.
    Orriss I, Syberg S, Wang N, Robaye B, Gartland A, Jorgensen N, Arnett T, Boeynaems JM (2011) Bone phenotypes of P2 receptor knockout mice. Front Biosci (Schol Ed) 3:1038–1046Google Scholar
  119. 119.
    Orriss IR, Wang N, Burnstock G, Arnett TR, Gartland A, Robaye B, Boeynaems J-M (2011) The P2Y6 receptor stimulates bone resorption by osteoclasts. Endocrinology 152:3706–3716PubMedGoogle Scholar
  120. 120.
    Su X, Floyd DH, Hughes A, Xiang J, Schneider JG, Uluckan O, Heller E, Deng H, Zou W, Craft CS, Wu K, Hirbe AC, Grabowska D, Eagleton MC, Townsley S, Collins L, Piwnica-Worms D, Steinberg TH, Novack DV, Conley PB, Hurchla MA, Rogers M, Weilbaecher KN (2012) The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling. J Clin Invest 122:3579–3592PubMedPubMedCentralGoogle Scholar
  121. 121.
    Wang N, Robaye B, Agrawal A, Skerry TM, Boeynaems JM, Gartland A (2012) Reduced bone turnover in mice lacking the P2Y13 receptor of ADP. Mol Endocrinol 26:142–152PubMedGoogle Scholar
  122. 122.
    Syberg S, Petersen S, Beck Jensen JE, Gartland A, Teilmann J, Chessell I, Steinberg TH, Schwarz P, Jorgensen NR (2012) Genetic background strongly influences the bone phenotype of P2X7 receptor knockout mice. J Osteoporos 2012:391097PubMedPubMedCentralGoogle Scholar
  123. 123.
    Nijweide PJ, Modderman WE, Hagenaars CE (1995) Extracellular adenosine triphosphate. A shock to hemopoietic cells. Clin Orthop Relat Res 92–102Google Scholar
  124. 124.
    Russell RG, Rogers MJ (1999) Bisphosphonates: from the laboratory to the clinic and back again. Bone 25:97–106PubMedGoogle Scholar
  125. 125.
    Coxon FP, Thompson K, Rogers MJ (2006) Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 6:307–312PubMedGoogle Scholar
  126. 126.
    Russell RG (2011) Bisphosphonates: The first 40 years. Bone 49:2–19PubMedGoogle Scholar
  127. 127.
    Dixon SJ, Sims SM (2000) P2 purinergic receptors on osteoblasts and osteoclasts: potential targets for drug development. Drug Dev Res 49:187–200Google Scholar
  128. 128.
    Steinberg TH, Jørgensen NR, Bong JS, Henriksen Z, Atal N, Lin GC, Bennett BD, Eriksen EF, Sørensen OH, Civitelli R (2001) P2-mediated responses in osteoclasts and osteoclast-like cells. Drug Dev Res 53:126–129Google Scholar
  129. 129.
    Burnstock G, Arnett TR (2006) Edited monograph: nucleotides and regulation of bone cell function. Taylor & Francis, Boca Raton, pp 1–207Google Scholar
  130. 130.
    Bowler WB, Buckley KA, Gartland A, Hipskind RA, Bilbe G, Gallagher JA (2001) Extracellular nucleotide signaling: a mechanism for integrating local and systemic responses in the activation of bone remodeling. Bone 28:507–512PubMedGoogle Scholar
  131. 131.
    Ferrier J (2001) Purinergic and pyrimidinergic receptor signaling in bone cells. In: Abbracchio MP, Williams M (eds) Handbook of experimental pharmacology, volume 151/I. Purinergic and pyrimidinergic signalling I—molecular, nervous and urinogenitary system function. Springer, Berlin, pp 393–406Google Scholar
  132. 132.
    Kaunitz JD, Yamaguchi DT (2008) TNAP, TrAP, ecto-purinergic signaling, and bone remodeling. J Cell Biochem 105:655–662PubMedGoogle Scholar
  133. 133.
    Komarova SV, Dixon SJ, Sims SM (2001) Osteoclast ion channels: potential targets for antiresorptive drugs. Curr Pharm Des 7:637–654PubMedGoogle Scholar
  134. 134.
    Naemsch LN, Dixon SJ, Sims SM (2001) Activity-dependent development of P2X7 current and Ca2+ entry in rabbit osteoclasts. J Biol Chem 276:39107–39114PubMedGoogle Scholar
  135. 135.
    Hoebertz A, Arnett TR, Burnstock G (2003) Regulation of bone resorption and formation by purines and pyrimidines. Trends Pharmacol Sci 24:290–297PubMedGoogle Scholar
  136. 136.
    Gartland A, Buckley KA, Hipskind RA, Bowler WB, Gallagher JA (2003) P2 receptors in bone-modulation of osteoclast formation and activity via P2X7 activation. Crit Rev Eukaryot Gene Expr 13:237–242PubMedGoogle Scholar
  137. 137.
    Ke HZ, Qi H, Weidema AF, Zhang Q, Panupinthu N, Crawford DT, Grasser WA, Paralkar VM, Li M, Audoly LP, Gabel CA, Jee WS, Dixon SJ, Sims SM, Thompson DD (2003) Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mol Endocrinol 17:1356–1367PubMedGoogle Scholar
  138. 138.
    Li J, Liu D, Ke HZ, Duncan RL, Turner CH (2005) The P2X7 nucleotide receptor mediates skeletal mechanotransduction. J Biol Chem 280:42952–42959PubMedGoogle Scholar
  139. 139.
    Grol MW, Panupinthu N, Korcok J, Sims SM, Dixon SJ (2009) Expression, signaling, and function of P2X7 receptors in bone. Purinergic Signal 5:205–221PubMedPubMedCentralGoogle Scholar
  140. 140.
    Spencer GJ, Hitchcock IS, Genever PG (2004) Emerging neuroskeletal signalling pathways: a review. FEBS Lett 559:6–12PubMedGoogle Scholar
  141. 141.
    Turner CH, Robling AG (2004) Exercise as an anabolic stimulus for bone. Curr Pharm Des 10:2629–2641PubMedGoogle Scholar
  142. 142.
    Jørgensen NR (2005) Short-range intercellular calcium signaling in bone. APMIS Suppl 5–36Google Scholar
  143. 143.
    Chan ES, Fernandez P, Cronstein BN (2007) Adenosine in inflammatory joint diseases. Purinergic Signal 3:145–152PubMedPubMedCentralGoogle Scholar
  144. 144.
    Supanchart C, Kornak U (2008) Ion channels and transporters in osteoclasts. Arch Biochem Biophys 473:161–165PubMedGoogle Scholar
  145. 145.
    Intini G (2009) The use of platelet-rich plasma in bone reconstruction therapy. Biomaterials 30:4956–4966PubMedGoogle Scholar
  146. 146.
    Sekrecka-Belniak A, Balcerzak M, Buchet R, Pikula S (2010) Active creatine kinase is present in matrix vesicles isolated from femurs of chicken embryo: implications for bone mineralization. Biochem Biophys Res Commun 391:1432–1436PubMedGoogle Scholar
  147. 147.
    Arnett TR (2010) Acidosis, hypoxia and bone. Arch Biochem Biophys 503:103–109PubMedGoogle Scholar
  148. 148.
    Varani K, Padovan M, Govoni M, Vincenzi F, Trotta F, Borea PA (2010) The role of adenosine receptors in rheumatoid arthritis. Autoimmun Rev 10:61–64PubMedGoogle Scholar
  149. 149.
    Lerner UH, Sahlberg K, Fredholm BB (1987) Characterization of adenosine receptors in bone. Studies on the effect of adenosine analogues on cyclic AMP formation and bone resorption in cultured mouse calvaria. Acta Physiol Scand 131:287–296PubMedGoogle Scholar
  150. 150.
    Shimegi S (1998) Mitogenic action of adenosine on osteoblast-like cells, MC3T3-E1. Calcif Tissue Int 62:418–425PubMedGoogle Scholar
  151. 151.
    Yu H, Ferrier J (1993) Osteoblast-like cells have a variable mixed population of purino/nucleotide receptors. FEBS Lett 328:209–214PubMedGoogle Scholar
  152. 152.
    Sistare FD, Rosenzweig BA, Contrera JG, Jordan B (1994) Separate P2T and P2U purinergic receptors with similar second messenger signalling pathways in UMR-106 osteoblasts. J Pharmacol Exp Ther 269:1049–1061PubMedGoogle Scholar
  153. 153.
    Gallinaro BJ, Reimer WJ, Dixon SJ (1995) Activation of protein kinase C inhibits ATP-induced [Ca2+]i elevation in rat osteoblastic cells: selective effects on P2Y and P2U signaling pathways. J Cell Physiol 162:305–314PubMedGoogle Scholar
  154. 154.
    Shimegi S (1996) ATP and adenosine act a mitogen for osteoblast-like cells (MC3T3-E1). Calcif Tissue Int 58:109–113PubMedGoogle Scholar
  155. 155.
    Suzuki A, Kotoyori J, Oiso Y, Kozawa O (1993) Prostaglandin E2 is a potential mediator of extracellular ATP action in osteoblast-like cells. Cell Adhes Commun 1:113–118PubMedGoogle Scholar
  156. 156.
    Bowler WB, Birch MA, Gallagher JA, Bilbe G (1995) Identification and cloning of human P2U purinoceptor present in osteoclastoma, bone, and osteoblasts. J Bone Miner Res 10:1137–1145PubMedGoogle Scholar
  157. 157.
    Dixon CJ, Bowler WB, Walsh CA, Gallagher JA (1997) Effects of extracellular nucleotides on single cells and populations of human osteoblasts: contribution of cell heterogeneity to relative potencies. Br J Pharmacol 120:777–780PubMedGoogle Scholar
  158. 158.
    Orriss I, Knight GE, Ramasingh S, Burnstock G, Arnett TR (2006) Osteoblast responses to nucleotides increase during differentiation. Bone 39:300–309PubMedGoogle Scholar
  159. 159.
    Strohbach CA, Genetos DC, Taylor AF, Donahue HJ (2004) Differentiation affects MC3T3-E1 mechanoresponsiveness and P2Y2 expression. J Bone Miner Res 19:S257Google Scholar
  160. 160.
    Nishii N, Nejime N, Yamauchi C, Yanai N, Shinozuka K, Nakabayashi T (2009) Effects of ATP on the intracellular calcium level in the osteoblastic TBR31-2 cell line. Biol Pharm Bull 32:18–23PubMedGoogle Scholar
  161. 161.
    Maier R, Glatz A, Mosbacher J, Bilbe G (1997) Cloning of P2Y6 cDNAs and identification of a pseudogene: comparison of P2Y receptor subtype expression in bone and brain tissues. Biochem Biophys Res Commun 240:298–302PubMedGoogle Scholar
  162. 162.
    Ihara H, Hirukawa K, Goto S, Togari A (2005) ATP-stimulated interleukin-6 synthesis through P2Y receptors on human osteoblasts. Biochem Biophys Res Commun 326:329–334PubMedGoogle Scholar
  163. 163.
    Buckley KA, Wagstaff SC, McKay G, Gaw A, Hipskind RA, Bilbe G, Gallagher JA, Bowler WB (2001) Parathyroid hormone potentiates nucleotide-induced [Ca2+]i release in rat osteoblasts independently of Gq activation or cyclic monophosphate accumulation. A mechanism for localizing systemic responses in bone. J Biol Chem 276:9565–9571PubMedGoogle Scholar
  164. 164.
    Jørgensen NR, Geist ST, Civitelli R, Steinberg TH (1997) ATP- and gap junction-dependent intercellular calcium signaling in osteoblastic cells. J Cell Biol 139:497–506PubMedPubMedCentralGoogle Scholar
  165. 165.
    Li DL, Liu X, Xia R, Ross C, Yang X, Jiang LH (2009) Pharmacological properties of ATP-sensitive purinergic receptors expressed in human G292 osteoblastic cells. Eur J Pharmacol 617:12–16PubMedGoogle Scholar
  166. 166.
    Hoebertz A, Townsend-Nicholson A, Glass R, Burnstock G, Arnett TR (2000) Expression of P2 receptors in bone and cultured bone cells. Bone 27:503–510PubMedGoogle Scholar
  167. 167.
    Orriss IR, Key ML, Brandao-Burch A, Burnstock G, Arnett TR (2012) The regulation of osteoblast function and bone mineralisation by extracellular nucleotides: the role of P2X receptors. Bone 51:389–400PubMedGoogle Scholar
  168. 168.
    Syberg S, Brandao-Burch A, Patel JJ, Hajjawi M, Arnett TR, Schwarz P, Jorgensen NR, Orriss IR (2012) Clopidogrel (Plavix®), a P2Y 12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo. J Bone Miner Res 27:2373–2386PubMedGoogle Scholar
  169. 169.
    Gartland A, Hipskind RA, Gallagher JA, Bowler WB (2001) Expression of a P2X7 receptor by a subpopulation of human osteoblasts. J Bone Miner Res 16:846–856PubMedGoogle Scholar
  170. 170.
    Gangadharan V, Nohe A, Duncan R (2011) ATP stimulates calveolar endocytosis of P2X7R in MC3T3-E1 osteoblasts. Biophys J 100:418Google Scholar
  171. 171.
    Nakamura E, Uezono Y, Narusawa K, Shibuya I, Oishi Y, Tanaka M, Yanagihara N, Nakamura T, Izumi F (2000) ATP activates DNA synthesis by acting on P2X receptors in human osteoblast-like MG-63 cells. Am J Physiol Cell Physiol 279:C510–C519PubMedGoogle Scholar
  172. 172.
    Alqallaf SM, Evans BA, Kidd EJ (2009) Atypical P2X receptor pharmacology in two human osteoblast-like cell lines. Br J Pharmacol 156:1124–1135PubMedPubMedCentralGoogle Scholar
  173. 173.
    Suzuki A, Shinoda J, Oiso Y, Kozawa O (1995) Mechanism of phospholipase D activation induced by extracellular ATP in osteoblast-like cells. J Endocrinol 145:81–86PubMedGoogle Scholar
  174. 174.
    Katz S, Boland R, Santillán G (2006) Modulation of ERK 1/2 and p38 MAPK signaling pathways by ATP in osteoblasts: involvement of mechanical stress-activated calcium influx, PKC and Src activation. Int J Biochem Cell Biol 38:2082–2091PubMedGoogle Scholar
  175. 175.
    Katz S, Boland R, Santillén G (2008) Purinergic (ATP) signaling stimulates JNK1 but not JNK2 MAPK in osteoblast-like cells: contribution of intracellular Ca2+ release, stress activated and L-voltage-dependent calcium influx, PKC and Src kinases. Arch Biochem Biophys 477:244–252PubMedGoogle Scholar
  176. 176.
    Katz S, Ayala V, Santillán G, Boland R (2011) Activation of the PI3K/Akt signaling pathway through P2Y2 receptors by extracellular ATP is involved in osteoblastic cell proliferation. Arch Biochem Biophys 513:144–152PubMedGoogle Scholar
  177. 177.
    Ayala-Peña VB, Scolaro LA, Santillán GE (2013) ATP and UTP stimulate bone morphogenetic protein-2, -4 and -5 gene expression and mineralization by rat primary osteoblasts involving PI3K/AKT pathway. Exp Cell Res 319:2028–2036PubMedGoogle Scholar
  178. 178.
    Gu Y, Xing YH, Donahue HJ, You J (2006) G-Protein coupled receptor kinase 2 inhibits ATP induced activation of ERKl/2 signaling pathway in osteoblasts. J Bone Miner Res 21:S258Google Scholar
  179. 179.
    Pines A, Romanello M, Cesaratto L, Damante G, Moro L, D'Andrea P, Tell G (2003) Extracellular ATP stimulates the early growth response protein 1 (Egr-1) via a protein kinase C-dependent pathway in the human osteoblastic HOBIT cell line. Biochem J 373:815–824PubMedPubMedCentralGoogle Scholar
  180. 180.
    Costessi A, Pines A, D'Andrea P, Romanello M, Damante G, Cesaratto L, Quadrifoglio F, Moro L, Tell G (2005) Extracellular nucleotides activate Runx2 in the osteoblast-like HOBIT cell line: a possible molecular link between mechanical stress and osteoblasts' response. Bone 36:418–432PubMedGoogle Scholar
  181. 181.
    Qi J, Chi L, Faber J, Koller B, Banes AJ (2007) ATP reduces gel compaction in osteoblast-populated collagen gels. J Appl Physiol 102:1152–1160PubMedGoogle Scholar
  182. 182.
    Qi J, Chi L, Wang J, Sumanasinghe R, Wall M, Tsuzaki M, Banes AJ (2009) Modulation of collagen gel compaction by extracellular ATP is MAPK and NF-κB pathways dependent. Exp Cell Res 315:1990–2000PubMedGoogle Scholar
  183. 183.
    Hirukawa K, Muraki K, Ohya S, Imaizumi Y, Togari A (2008) Electrophysiological properties of a novel Ca2+-activated K+ channel expressed in human osteoblasts. Calcif Tissue Int 83:222–229PubMedGoogle Scholar
  184. 184.
    Silber AS, Pfau B, Tan TW, Jacob R, Jones D, Meyer T (2012) Dynamic redistribution of paxillin in bovine osteoblasts stimulated with adenosine 5'-triphosphate. J Mol Histol 43:571–580PubMedPubMedCentralGoogle Scholar
  185. 185.
    Kaplan AD, Reimer WJ, Feldman RD, Dixon SJ (1995) Extracellular nucleotides potentiate the cytosolic Ca2+, but not cyclic adenosine 3′,5′-monophosphate response to parathyroid hormone in rat osteoblastic cells. Endocrinology 136:1674–1685PubMedGoogle Scholar
  186. 186.
    Sistare FD, Rosenzweig BA, Contrera JG (1995) P2 purinergic receptors potentiate parathyroid hormone receptor-mediated increases in intracellular calcium and inositol triphosphate in UMR-106 rat osteoblasts. Endocrinology 136:4489–4497PubMedGoogle Scholar
  187. 187.
    Bowler WB, Dixon CJ, Halleux C, Maier R, Bilbe G, Fraser WD, Gallagher JA, Hipskind RA (1999) Signaling in human osteoblasts by extracellular nucleotides. Their weak induction of the c-fos proto-oncogene via Ca2+ mobilization is strongly potentiated by a parathyroid hormone/cAMP-dependent protein kinase pathway independently of mitogen-activated protein kinase. J Biol Chem 274:14315–14324PubMedGoogle Scholar
  188. 188.
    Nakao Y, Koike T, Ohta Y, Manaka T, Imai Y, Takaoka K (2009) Parathyroid hormone enhances bone morphogenetic protein activity by increasing intracellular 3′,5′-cyclic adenosine monophosphate accumulation in osteoblastic MC3T3-E1 cells. Bone 44:872–877PubMedGoogle Scholar
  189. 189.
    Roy AA, Nunn C, Ming H, Zou MX, Penninger J, Kirshenbaum LA, Dixon SJ, Chidiac P (2006) Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts. J Biol Chem 281:32684–32693PubMedGoogle Scholar
  190. 190.
    Watanabe-Tomita Y, Suzuki A, Shinoda J, Oiso Y, Kozawa O (1997) Arachidonic acid release induced by extracellular ATP in osteoblasts: role of phospholipase D. Prostaglandins Leukot Essent Fatty Acids 57:335–339PubMedGoogle Scholar
  191. 191.
    Pacheco-Pantoja EL, Dillon JP, Wilson PJM, Ranganath L, Fraser WD, Gallagher JA (2009) Extracellular ATP, signalling through P2 receptors, synergises with glucose-dependent insulinotropic polypeptide to induce c-fos in osteoblastic cells. Bone 44:S356Google Scholar
  192. 192.
    You J, Jacobs CR, Steinberg TH, Donahue HJ (2002) P2Y purinoceptors are responsible for oscillatory fluid flow-induced intracellular calcium mobilization in osteoblastic cells. J Biol Chem 277:48724–48729PubMedGoogle Scholar
  193. 193.
    Genetos DC, Kephart CJ, Zhang Y, Yellowley CE, Donahue HJ (2007) Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. J Cell Physiol 212:207–214PubMedPubMedCentralGoogle Scholar
  194. 194.
    Henriksen Z, Hiken JF, Steinberg TH, Jørgensen NR (2006) The predominant mechanism of intercellular calcium wave propagation changes during long-term culture of human osteoblast-like cells. Cell Calcium 39:435–444PubMedGoogle Scholar
  195. 195.
    Huo B, Lu XL, Costa KD, Xu Q, Guo XE (2010) An ATP-dependent mechanism mediates intercellular calcium signaling in bone cell network under single cell nanoindentation. Cell Calcium 47:234–241PubMedPubMedCentralGoogle Scholar
  196. 196.
    Huo B, Lu XL, Guo XE (2010) Intercellular calcium wave propagation in linear and circuit-like bone cell networks. Philos Transact A Math Phys Eng Sci 368:617–633Google Scholar
  197. 197.
    Gardinier JD, Majumdar S, Duncan RL, Wang L (2009) Cyclic hydraulic pressure and fluid flow differentially modulate cytoskeleton re-organization in MC3T3 osteoblasts. Cell Mol Bioeng 2:133–143PubMedPubMedCentralGoogle Scholar
  198. 198.
    Nam SH, Jung SY, Yoo CM, Ahn EH, Suh CK (2002) H2O2 enhances Ca2+ release from osteoblast internal stores. Yonsei Med J 43:229–235PubMedGoogle Scholar
  199. 199.
    D'Andrea P, Romanello M, Bicego M, Steinberg TH, Tell G (2006) H2O2 activates purinergic signalling in osteoblasts. Purinergic Signal 2:221Google Scholar
  200. 200.
    D'Andrea P, Romanello M, Bicego M, Steinberg TH, Tell G (2008) H2O2 modulates purinergic-dependent calcium signalling in osteoblast-like cells. Cell Calcium 43:457–468PubMedGoogle Scholar
  201. 201.
    Nakano Y, Addison WN, Kaartinen MT (2007) ATP-mediated mineralization of MC3T3-E1 osteoblast cultures. Bone 41:549–561PubMedGoogle Scholar
  202. 202.
    Jones SJ, Gray C, Boyde A, Burnstock G (1997) Purinergic transmitters inhibit bone formation by cultured osteoblasts. Bone 21:393–399PubMedGoogle Scholar
  203. 203.
    Orriss IR, Utting JC, Brandao-Burch A, Colston K, Grubb BR, Burnstock G, Arnett TR (2007) Extracellular nucleotides block bone mineralisation in vitro: evidence for dual inhibitory mechanisms involving both P2Y2 receptors and pyrophosphate. Endocrinology 148:4208–4216PubMedGoogle Scholar
  204. 204.
    Orriss IR, Arnett TR (2010) Extracellular nucleotides regulate the expression and activity of ecto-nucleotidases by osteoblasts. Bone 46:S55Google Scholar
  205. 205.
    Orriss IR, Key ML, Hajjawi MOR, Arnett TR (2013) Extracellular ATP released by osteoblasts is a key local inhibitor of mineralisation. PLoS One, 8:e69057Google Scholar
  206. 206.
    Jørgensen NR, Grove EL, Schwarz P, Vestergaard P (2012) Clopidogrel and the risk of osteoporotic fractures: a nationwide cohort study. J Intern Med 272:385–393PubMedGoogle Scholar
  207. 207.
    Biver G, Wang N, Gartland A, Orriss I, Arnett TR, Boeynaems JM, Robaye B (2013) Role of the P2Y13 receptor in the differentiation of bone marrow stromal cells into osteoblasts and adipocytes. Stem Cells. doi:10.1002/stem.1411
  208. 208.
    Henriksen BM, Nissen N, Jørgensen NR (2006) Functional P2X7 purinergic receptors are expressed in differentiated human osteoblasts. J Bone Miner Res 21:S258Google Scholar
  209. 209.
    Panupinthu N, Rogers JT, Zhao L, Solano-Flores LP, Possmayer F, Sims SM, Dixon SJ (2008) P2X7 receptors on osteoblasts couple to production of lysophosphatidic acid: a signaling axis promoting osteogenesis. J Cell Biol 181:859–871PubMedPubMedCentralGoogle Scholar
  210. 210.
    Panupinthu N, Zhao L, Possmayer F, Ke HZ, Sims SM, Dixon SJ (2007) P2X7 nucleotide receptors mediate blebbing in osteoblasts through a pathway involving lysophosphatidic acid. J Biol Chem 282:3403–3412PubMedGoogle Scholar
  211. 211.
    Brandao-Burch A, Key ML, Patel JJ, Arnett TR, Orriss IR (2012) The P2X7 receptor is an important regulator of extracellular ATP levels. Front Endocrinol (Lausanne) 3:41Google Scholar
  212. 212.
    Rumney RM, Wang N, Gartland A (2010) The role of P2X 7 receptors in ATP release from osteoblasts. Purinergic Signal 6:129Google Scholar
  213. 213.
    Genetos DC, Karin NJ, Geist DJ, Donahue HJ, Duncan RL (2011) Purinergic signaling is required for fluid shear stress-induced NF-κB translocation in osteoblasts. Exp Cell Res 317:737–744PubMedPubMedCentralGoogle Scholar
  214. 214.
    Grol MW, Zelner I, Dixon SJ (2012) P2X7-mediated calcium influx triggers a sustained, PI3K-dependent increase in metabolic acid production by osteoblast-like cells. Am J Physiol Endocrinol Metab 302:E561–E575PubMedGoogle Scholar
  215. 215.
    Petersen S, Syberg S, Henriksen Z, Schwarz P, Jensen JE, Sørensen OH, Jørgensen NR (2007) The purinergic P2X7 receptor is responsible for ovariectomy-induced bone loss in mice. J Bone Miner Res 21:S258Google Scholar
  216. 216.
    Li J, Meyer R, Duncan RL, Turner CH (2009) P2X7 nucleotide receptor plays an important role in callus remodeling during fracture repair. Calcif Tissue Int 84:405–412PubMedGoogle Scholar
  217. 217.
    Genetos DC, Geist DJ, Liu D, Donahue HJ, Duncan RL (2005) Fluid shear-induced ATP secretion mediates prostaglandin release in MC3T3-E1 osteoblasts. J Bone Miner Res 20:41–49PubMedPubMedCentralGoogle Scholar
  218. 218.
    Liu D, Genetos DC, Shao Y, Geist DJ, Li J, Ke HZ, Turner CH, Duncan RL (2008) Activation of extracellular-signal regulated kinase (ERK1/2) by fluid shear is Ca2+- and ATP-dependent in MC3T3-E1 osteoblasts. Bone 42:644–652PubMedPubMedCentralGoogle Scholar
  219. 219.
    Okumura H, Shiba D, Kubo T, Yokoyama T (2008) P2X7 receptor as sensitive flow sensor for ERK activation in osteoblasts. Biochem Biophys Res Commun 372:486–490PubMedGoogle Scholar
  220. 220.
    Nicke A, Kuan YH, Masin M, Rettinger J, Marquez-Klaka B, Bender O, Gorecki DC, Murrell-Lagnado RD, Soto F (2009) A functional P2X7 splice variant with an alternative transmembrane domain 1 escapes gene inactivation in P2X7 knock-out mice. J Biol Chem 284:25813–25822PubMedPubMedCentralGoogle Scholar
  221. 221.
    Husted LB, Gonzalez-Bofill N, Carstens M, Stenkjaer L, Langdahl BL (2007) Gain-of-function polymorphisms in the P2X7 purinergic receptor are associated with increased bone mass. Calcif Tissue Int 80:S99–S100Google Scholar
  222. 222.
    Ohlendorff SD, Tofteng CL, Jensen JE, Petersen S, Civitelli R, Fenger M, Abrahamsen B, Hermann AP, Eiken P, Jorgensen NR (2007) Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment. Pharmacogenet Genomics 17:555–567PubMedGoogle Scholar
  223. 223.
    Husted LB, Harsløf T, Stenkjær L, Carstens M, Jørgensen NR, Langdahl BL (2013) Functional polymorphisms in the P2X7 receptor gene are associated with osteoporosis. Osteoporos Int 24:949–959PubMedGoogle Scholar
  224. 224.
    Gartland A, Skarratt KK, Hocking LJ, Parsons C, Stokes L, Jorgensen NR, Fraser WD, Reid DM, Gallagher JA, Wiley JS (2012) Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women. Eur J Hum Genet 20:559–564PubMedPubMedCentralGoogle Scholar
  225. 225.
    Romanello M, Pani B, Bicego M, D'Andrea P (2001) Mechanically induced ATP release from human osteoblastic cells. Biochem Biophys Res Commun 289:1275–1281PubMedGoogle Scholar
  226. 226.
    Romanello M, Codognotto A, Bicego M, Pines A, Tell G, D'Andrea P (2005) Autocrine/paracrine stimulation of purinergic receptors in osteoblasts: contribution of vesicular ATP release. Biochem Biophys Res Commun 331:1429–1438PubMedGoogle Scholar
  227. 227.
    Gartland A, Burrell HE, Dillon JP, Mwaura BK, Hayton MJ, Gallagher JA (2006) Release of ATP from human osteoblasts occurs via a calcium dependent, exocytotic vesicular mechanism. Purinergic Signal 2:4Google Scholar
  228. 228.
    Orriss IR, Knight GE, Utting JC, Taylor SEB, Burnstock G, Arnett TR (2009) Hypoxia stimulates vesicular ATP release from rat osteoblasts. J Cell Physiol 220:155–162PubMedGoogle Scholar
  229. 229.
    Sabirov RZ, Okada Y (2009) The maxi-anion channel: a classical channel playing novel roles through an unidentified molecular entity. J Physiol Sci 59:3–21PubMedGoogle Scholar
  230. 230.
    Thi MM, Islam S, Suadicani SO, Spray DC (2012) Connexin43 and pannexin1 channels in osteoblasts: who is the "hemichannel"? J Membr Biol 245:401–409PubMedPubMedCentralGoogle Scholar
  231. 231.
    Shao Y, Fomin VP, Farach-Carson MC, Duncan RL (2008) Ahnak regulates calcium signaling and ATP release in osteoblasts in response to mechanical stimulation. J Bone Miner Res 23:S139Google Scholar
  232. 232.
    Asada K, Obata K, Horiguchi K, Takaki M (2012) Age-related changes in afferent responses in sensory neurons to mechanical stimulation of osteoblasts in coculture system. Am J Physiol Cell Physiol 302:C757–C765PubMedGoogle Scholar
  233. 233.
    Hecht E, Liedert A, Ignatius A, Mizaikoff B, Kranz C (2013) Local detection of mechanically induced ATP release from bone cells with ATP microbiosensors. Biosens Bioelectron 44:27–33PubMedGoogle Scholar
  234. 234.
    Rumney RM, Sunters A, Reilly GC, Gartland A (2012) Application of multiple forms of mechanical loading to human osteoblasts reveals increased ATP release in response to fluid flow in 3D cultures and differential regulation of immediate early genes. J Biomech 45:549–554PubMedPubMedCentralGoogle Scholar
  235. 235.
    Biswas P, Zanello LP (2009) 1α,25(OH)2 vitamin D3 induction of ATP secretion in osteoblasts. J Bone Miner Res 24:1450–1460PubMedPubMedCentralGoogle Scholar
  236. 236.
    Biswas P, Zanello LP (2006) Vitamin D3 rapidly regulates ATP release via L-Ca and CIC-3 channels in osteoblasts. Biophys J 172AGoogle Scholar
  237. 237.
    Hayton MJ, Dillon JP, Glynn D, Curran JM, Gallagher JA, Buckley KA (2005) Involvement of adenosine 5′-triphosphate in ultrasound-induced fracture repair. Ultrasound Med Biol 31:1131–1138PubMedGoogle Scholar
  238. 238.
    Alvarenga ÉC, Rodrigues R, Caricati-Neto A, Silva-Filho FC, Paredes-Gamero EJ, Ferreira AT (2010) Low-intensity pulsed ultrasound-dependent osteoblast proliferation occurs by via activation of the P2Y receptor: role of the P2Y1 receptor. Bone 46:355–362PubMedGoogle Scholar
  239. 239.
    Romanello M, Bivi N, Pines A, Deganuto M, Quadrifoglio F, Moro L, Tell G (2006) Bisphosphonates activate nucleotide receptors signaling and induce the expression of Hsp90 in osteoblast-like cell lines. Bone 39:739–753PubMedGoogle Scholar
  240. 240.
    Zimmermann H, Zebisch M, Strater N (2012) Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 8:437–502PubMedPubMedCentralGoogle Scholar
  241. 241.
    Buckley KA, Golding SL, Rice JM, Dillon JP, Gallagher JA (2003) Release and interconversion of P2 receptor agonists by human osteoblast-like cells. FASEB J 17:1401–1410PubMedGoogle Scholar
  242. 242.
    Mackenzie NC, Zhu D, Milne EM, vańt Hof R, Martin A, Darryl QL, Millán JL, Farquharson C, Macrae VE (2012) Altered bone development and an increase in FGF-23 expression in Enpp1 −/− mice. PLoS One 7:e32177PubMedPubMedCentralGoogle Scholar
  243. 243.
    Ham J, Evans BA (2012) An emerging role for adenosine and its receptors in bone homeostasis. Front Endocrinol (Lausanne) 3:113Google Scholar
  244. 244.
    Evans BA, Elford C, Pexa A, Francis K, Hughes AC, Deussen A, Ham J (2006) Human osteoblast precursors produce extracellular adenosine, which modulates their secretion of IL-6 and osteoprotegerin. J Bone Miner Res 21:228–236PubMedGoogle Scholar
  245. 245.
    Costa MA, Barbosa A, Neto E, Sá-e-Sousa A, Freitas R, Neves JM, Magalhães-Cardoso T, Ferreirinha F, Correia-de-Sá P (2011) On the role of subtype selective adenosine receptor agonists during proliferation and osteogenic differentiation of human primary bone marrow stromal cells. J Cell Physiol 226:1353–1366PubMedGoogle Scholar
  246. 246.
    Takedachi M, Oohara H, Smith BJ, Iyama M, Kobashi M, Maeda K, Long CL, Humphrey MB, Stoecker BJ, Toyosawa S, Thompson LF, Murakami S (2012) CD73-generated adenosine promotes osteoblast differentiation. J Cell Physiol 227:2622–2631PubMedPubMedCentralGoogle Scholar
  247. 247.
    Carroll SH, Wigner NA, Kulkarni N, Johnston-Cox H, Gerstenfeld LC, Ravid K (2012) A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J Biol Chem 287:15718–15727PubMedPubMedCentralGoogle Scholar
  248. 248.
    Fatokun AA, Stone TW, Smith RA (2006) Hydrogen peroxide-induced oxidative stress in MC3T3-E1 cells: The effects of glutamate and protection by purines. Bone 39:542–551PubMedGoogle Scholar
  249. 249.
    Huo B, Lu XL, Hung CT, Costa KD, Xu Q, Whitesides GM, Guo XE (2008) Fluid flow induced calcium response in bone cell network. Cell Mol Bioeng 1:58–66PubMedPubMedCentralGoogle Scholar
  250. 250.
    Thompson WR, Majid AS, Czymmek KJ, Ruff AL, García J, Duncan RL, Farach-Carson MC (2011) Association of the α2δ1 subunit with Cav3.2 enhances membrane expression and regulates mechanically induced ATP release in MLO-Y4 osteocytes. J Bone Miner Res 26:2125–2139PubMedGoogle Scholar
  251. 251.
    Kringelbach TM, Schwarz P, Novak I, Bonewald LF, Vang O, Jørgensen NR (2008) P2 receptors are functionally expressed in MLO-Y4 osteocytes. Purinergic Signal 4:S173–S174Google Scholar
  252. 252.
    Kringelbach TM, Novak I, Bonewald LF, Vang O, Schwarz P, Jørgensen NR (2012) UTP and mechanical stimulation induce ATP release from osteocytes. Bone 50:S95Google Scholar
  253. 253.
    Yu H, Ferrier J (1995) Osteoclast ATP receptor activation leads to a transient decrease in intracellular pH. J Cell Sci 108:3051–3058PubMedGoogle Scholar
  254. 254.
    Weidema AF, Barbera J, Dixon SJ, Sims SM (1997) Extracellular nucleotides activate non-selective cation and Ca2+-dependent K+ channels in rat osteoclasts. J Physiol 503:303–315PubMedPubMedCentralGoogle Scholar
  255. 255.
    Wiebe SH, Sims SM, Dixon SJ (1999) Calcium signalling via multiple P2 purinoceptor subtypes in rat osteoclasts. Cell Physiol Biochem 9:323–337PubMedGoogle Scholar
  256. 256.
    Naemsch LN, Weidema AF, Sims SM, Underhill TM, Dixon SJ (1999) P2X4 purinoceptors mediate an ATP-activated, non-selective cation current in rabbit osteoclasts. J Cell Sci 112:4425–4435PubMedGoogle Scholar
  257. 257.
    Weidema AF, Dixon SJ, Sims SM (2001) Activation of P2Y but not P2X4 nucleotide receptors causes elevation of [Ca2+]i in mammalian osteoclasts. Am J Physiol Cell Physiol 280:C1531–C1539PubMedGoogle Scholar
  258. 258.
    Buckley KA, Hipskind RA, Gartland A, Bowler WB, Gallagher JA (2002) Adenosine triphosphate stimulates human osteoclast activity via upregulation of osteoblast-expressed receptor activator of nuclear factor-κB ligand. Bone 31:582–590PubMedGoogle Scholar
  259. 259.
    Bowler WB, Littlewood-Evans A, Bilbe G, Gallagher JA, Dixon CJ (1998) P2Y2 receptors are expressed by human osteoclasts of giant cell tumor but do not mediate ATP-induced bone resorption. Bone 22:195–200PubMedGoogle Scholar
  260. 260.
    Wildman SS, King BF, Burnstock G (1998) Zn2+ modulation of ATP-responses at recombinant P2X2 receptors and its dependence on extracellular pH. Br J Pharmacol 123:1214–1220PubMedPubMedCentralGoogle Scholar
  261. 261.
    Hoebertz A, Meghji S, Burnstock G, Arnett TR (2001) Extracellular ADP is a powerful osteolytic agent: evidence for signaling through the P2Y1 receptor on bone cells. FASEB J 15:1139–1148PubMedGoogle Scholar
  262. 262.
    Hollopeter G, Jantzen H-M, Vincent D, Li G, England L, Ramakrishnan V, Yang R-B, Nurden P, Nurden A, Julius D, Conley PB (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207PubMedGoogle Scholar
  263. 263.
    Korcok J, Raimundo LN, Ke HZ, Sims SM, Dixon SJ (2004) Extracellular nucleotides act through P2X7 receptors to activate NF-κB in osteoclasts. J Bone Miner Res 19:642–651PubMedGoogle Scholar
  264. 264.
    Weidema AF, Dixon SJ, Sims SM (2000) Electrophysiological characterization of ion channels in osteoclasts isolated from human deciduous teeth. Bone 27:5–11PubMedGoogle Scholar
  265. 265.
    Korcok J, Raimundo LN, Du X, Sims SM, Dixon SJ (2005) P2Y6 nucleotide receptors activate NF-κB and increase survival of osteoclasts. J Biol Chem 280:16909–16915PubMedGoogle Scholar
  266. 266.
    Naemsch LN, Du X, Sims SM, Dixon SJ (2001) P2 nucleotide receptors in osteoclasts. Drug Dev Res 130–139Google Scholar
  267. 267.
    Gartland A, Buckley KA, Bowler WB, Gallagher JA (2003) Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro. Calcif Tissue Int 73:361–369PubMedGoogle Scholar
  268. 268.
    Penolazzi L, Bianchini E, Lambertini E, Baraldi PG, Romagnoli R, Piva R, Gambari R (2005) N-Arylpiperazine modified analogues of the P2X7 receptor KN-62 antagonist are potent inducers of apoptosis of human primary osteoclasts. J Biomed Sci 12:1013–1020PubMedGoogle Scholar
  269. 269.
    Hiken JF, Steinberg TH (2004) ATP downregulates P2X7 and inhibits osteoclast formation in RAW cells. Am J Physiol Cell Physiol 287:C403–C412PubMedGoogle Scholar
  270. 270.
    Armstrong S, Pereverzev A, Dixon SJ, Sims SM (2009) Activation of P2X7 receptors causes isoform-specific translocation of protein kinase C in osteoclasts. J Cell Sci 122:136–144PubMedGoogle Scholar
  271. 271.
    Jorgensen NR, Henriksen Z, Sorensen OH, Eriksen EF, Civitelli R, Steinberg TH (2002) Intercellular calcium signaling occurs between human osteoblasts and osteoclasts and requires activation of osteoclast P2X7 receptors. J Biol Chem 277:7574–7580PubMedGoogle Scholar
  272. 272.
    Hazama R, Qu X, Yokoyama K, Tanaka C, Kinoshita E, He J, Takahashi S, Tohyama K, Yamamura H, Tohyama Y (2009) ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk. Genes Cells 14:871–884PubMedGoogle Scholar
  273. 273.
    Pellegatti P, Falzoni S, Donvito G, Lemaire I, Di Virgilio F (2011) P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration. FASEB J 25:1264–1274PubMedGoogle Scholar
  274. 274.
    Morimoto R, Uehara S, Yatsushiro S, Juge N, Hua Z, Senoh S, Echigo N, Hayashi M, Mizoguchi T, Ninomiya T, Udagawa N, Omote H, Yamamoto A, Edwards RH, Moriyama Y (2006) Secretion of L-glutamate from osteoclasts through transcytosis. EMBO J 25:4175–4186PubMedPubMedCentralGoogle Scholar
  275. 275.
    Bond A, Wilson PJM, Dillon JP, Pacheco-Pantoja EL, Fraser WD, Jarvis JC, Gallagher JA (2010) ATP is released from osteoclasts and osteoblasts and sensitises bone to the action of PTH and other systemic hormones. Purinergic Signal 6:143–144Google Scholar
  276. 276.
    Cherruau M, Facchinetti P, Baroukh B, Saffar JL (1999) Chemical sympathectomy impairs bone resorption in rats: a role for the sympathetic system on bone metabolism. Bone 25:545–551PubMedGoogle Scholar
  277. 277.
    Binderman I, Bahar H, Jacob-Hirsch J, Zeligson S, Amariglio N, Rechavi G, Shoham S, Yaffe A (2007) P2X4 is up-regulated in gingival fibroblasts after periodontal surgery. J Dent Res 86:181–185PubMedGoogle Scholar
  278. 278.
    Miyazaki T, Iwasawa M, Nakashima T, Mori S, Shigemoto K, Nakamura H, Katagiri H, Takayanagi H, Tanaka S (2012) Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption. J Biol Chem 287:37808–37823PubMedPubMedCentralGoogle Scholar
  279. 279.
    Räikkönen J, Crockett JC, Rogers MJ, Mönkkönen H, Auriola S, Mönkkönen J (2009) Zoledronic acid induces formation of a pro-apoptotic ATP analogue and isopentenyl pyrophosphate in osteoclasts in vivo and in MCF-7 cells in vitro. Br J Pharmacol 157:427–435PubMedPubMedCentralGoogle Scholar
  280. 280.
    Lerner U, Fredholm BB (1983) Studies on the mechanisms by which 2-chloroadenosine stimulates bone resorption in tissue culture. Biochim Biophys Acta 757:226–234PubMedGoogle Scholar
  281. 281.
    Lerner U, Fredholm BB (1985) Prostaglandin E2 and 2-chloroadenosine act in concert to stimulate bone resorption in cultured murine calvarial bones. Biochem Pharmacol 34:937–940PubMedGoogle Scholar
  282. 282.
    Kara FM, Chitu V, Sloane J, Axelrod M, Fredholm BB, Stanley ER, Cronstein BN (2010) Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. FASEB J 24:2325–2333PubMedPubMedCentralGoogle Scholar
  283. 283.
    He W, Cronstein BN (2012) Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling. Purinergic Signal 8:327–337PubMedPubMedCentralGoogle Scholar
  284. 284.
    Kara FM, Doty SB, Boskey A, Goldring S, Zaidi M, Fredholm BB, Cronstein BN (2010) Adenosine A1 receptors regulate bone resorption in mice: adenosine A1 receptor blockade or deletion increases bone density and prevents ovariectomy-induced bone loss in adenosine A1 receptor-knockout mice. Arthritis Rheum 62:534–541PubMedPubMedCentralGoogle Scholar
  285. 285.
    Mediero A, Kara FM, Wilder T, Cronstein BN (2012) Adenosine A2A receptor ligation inhibits osteoclast formation. Am J Pathol 180:775–786PubMedPubMedCentralGoogle Scholar
  286. 286.
    Mediero A, Frenkel SR, Wilder T, He W, Mazumder A, Cronstein BN (2012) Adenosine A2A receptor activation prevents wear particle-induced osteolysis. Sci Transl Med 135ra65:4Google Scholar
  287. 287.
    Teramachi J, Kukita A, Qu P, Wada N, Li YJ, Nakamura S, Kukita T (2013) Adenosine blocks aminopterin-induced suppression of osteoclast differentiation. J Bone Miner Metab 31:64–70PubMedGoogle Scholar
  288. 288.
    Mansour A, Abou-Ezzi G, Sitnicka E, Jacobsen SE, Wakkach A, Blin-Wakkach C (2012) Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J Exp Med 209:537–549PubMedPubMedCentralGoogle Scholar
  289. 289.
    Riddle RC, Taylor AF, Rogers JR, Donahue HJ (2007) ATP release mediates fluid flow-induced proliferation of human bone marrow stromal cells. J Bone Miner Res 22:589–600PubMedGoogle Scholar
  290. 290.
    Rossi L, Manfredini R, Bertolini F, Ferrari D, Fogli M, Zini R, Salati S, Salvestrini V, Gulinelli S, Adinolfi E, Ferrari S, Di Virgilio F, Baccarani M, Lemoli RM (2007) The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration. Blood 109:533–542PubMedGoogle Scholar
  291. 291.
    Noronha-Matos JB, Costa MA, Magalhães-Cardoso MT, Ferreirinha F, Pelletier J, Freitas R, Neves JM, Sévigny J, Correia-de-Sá P (2012) Role of ecto-NTPDases on UDP-sensitive P2Y6 receptor activation during osteogenic differentiation of primary bone marrow stromal cells from postmenopausal women. J Cell Physiol 227:2694–2709PubMedGoogle Scholar
  292. 292.
    Zippel N, Limbach CA, Ratajski N, Urban C, Luparello C, Pansky A, Kassack MU, Tobiasch E (2012) Purinergic receptors influence the differentiation of human mesenchymal stem cells. Stem Cells Dev 21:884–900PubMedGoogle Scholar
  293. 293.
    Ferrari D, Gulinelli S, Salvestrini V, Lucchetti G, Zini R, Manfredini R, Caione L, Piacibello W, Ciciarello M, Rossi L, Idzko M, Ferrari S, Di Virgilio F, Lemoli RM (2011) Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines. Exp Hematol 39(360–74):374Google Scholar
  294. 294.
    Mohamadnejad M, Sohail MA, Watanabe A, Krause DS, Swenson ES, Mehal WZ (2010) Adenosine inhibits chemotaxis and induces hepatocyte-specific genes in bone marrow mesenchymal stem cells. Hepatology 51:963–973PubMedPubMedCentralGoogle Scholar
  295. 295.
    Leong WS, Russell RG, Caswell AM (1990) Extracellular ATP stimulates resorption of bovine nasal cartilage. Biochem Soc Trans 18:951–952PubMedGoogle Scholar
  296. 296.
    Caswell AM, Leong WS, Russell RG (1991) Evidence for the presence of P2-purinoceptors at the surface of human articular chondrocytes in monolayer culture. Biochim Biophys Acta 1074:151–158PubMedGoogle Scholar
  297. 297.
    Caswell AM, Leong WS, Russell RG (1992) Interleukin-1β enhances the response of human articular chondrocytes to extracellular ATP. Biochim Biophys Acta 1137:52–58PubMedGoogle Scholar
  298. 298.
    Kaplan AD, Kilkenny DM, Hill DJ, Dixon SJ (1996) Extracellular nucleotides act through P2U purinoceptors to elevate [Ca2+]i and enhance basic fibroblast growth factor-induced proliferation in sheep chondrocytes. Endocrinology 137:4757–4766PubMedGoogle Scholar
  299. 299.
    Koolpe M, Benton HP (1997) Calcium-mobilizing purine receptors on the surface of mammalian articular chondrocytes. J Orthop Res 15:204–212PubMedGoogle Scholar
  300. 300.
    Koolpe M, Pearson D, Benton HP (1999) Expression of both P1 and P2 purine receptor genes by human articular chondrocytes and profile of ligand-mediated prostaglandin E2 release. Arthritis Rheum 42:258–267PubMedGoogle Scholar
  301. 301.
    Kudirka JC, Panupinthu N, Tesseyman MA, Dixon SJ, Bernier SM (2007) P2Y nucleotide receptor signaling through MAPK/ERK is regulated by extracellular matrix: involvement of β3 integrins. J Cell Physiol 213:54–64PubMedGoogle Scholar
  302. 302.
    Knight MM, McGlashan SR, Garcia M, Jensen CG, Poole CA (2009) Articular chondrocytes express connexin 43 hemichannels and P2 receptors—a putative mechanoreceptor complex involving the primary cilium? J Anat 214:275–283PubMedPubMedCentralGoogle Scholar
  303. 303.
    Varani K, De Mattei M, Vincenzi F, Tosi A, Gessi S, Merighi S, Pellati A, Masieri F, Ongaro A, Borea PA (2008) Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes. Osteoarth Cart 16:1421–1429Google Scholar
  304. 304.
    Bulman WA, Iannotti JP, Glowacki K, Bleuit J, Clark CC (1995) Serum fractions and related agonists with calcium-mobilizing activity in the bovine growth plate chondrocyte. J Orthop Res 13:220–229PubMedGoogle Scholar
  305. 305.
    Hung CT, Allen FD, Mansfield KD, Shapiro IM (1997) Extracellular ATP modulates [Ca2+]i in retinoic acid-treated embryonic chondrocytes. Am J Physiol 272:C1611–C1617PubMedGoogle Scholar
  306. 306.
    Elfervig MK, Graff RD, Lee GM, Kelley SS, Sood A, Banes AJ (2001) ATP induces Ca2+ signaling in human chondrons cultured in three-dimensional agarose films. Osteoarth Cart 9:518–526Google Scholar
  307. 307.
    Kono T, Nishikori T, Kataoka H, Uchio Y, Ochi M, Enomoto K (2006) Spontaneous oscillation and mechanically induced calcium waves in chondrocytes. Cell Biochem Funct 24:103–111PubMedGoogle Scholar
  308. 308.
    Hsu HH (1992) Further studies on ATP-mediated CA deposition by isolated matrix vesicles. Bone Miner 17:279–283PubMedGoogle Scholar
  309. 309.
    Ryan LM, Kurup IV, Derfus BA, Kushnaryov VM (1992) ATP-induced chondrocalcinosis. Arthritis Rheum 35:1520–1525PubMedGoogle Scholar
  310. 310.
    Hsu HH, Anderson HC (1996) Evidence of the presence of a specific ATPase responsible for ATP-initiated calcification by matrix vesicles isolated from cartilage and bone. J Biol Chem 271:26383–26388PubMedGoogle Scholar
  311. 311.
    Meyer MP, Swann K, Burnstock G, Clarke JDW (2001) The extracellular ATP receptor, cP2Y1, inhibits cartilage formation in micromass cultures of chick limb mesenchyme. Dev Dyn 222:494–505PubMedGoogle Scholar
  312. 312.
    Brown CJ, Caswell AM, Rahman S, Russell RG, Buttle DJ (1997) Proteoglycan breakdown from bovine nasal cartilage is increased, and from articular cartilage is decreased, by extracellular ATP. Biochim Biophys Acta 1362:208–220PubMedGoogle Scholar
  313. 313.
    Berenbaum F, Humbert L, Bereziat G, Thirion S (2003) Concomitant recruitment of ERK1/2 and p38 MAPK signalling pathway is required for activation of cytoplasmic phospholipase A2 via ATP in articular chondrocytes. J Biol Chem 278:13680–13687PubMedGoogle Scholar
  314. 314.
    Croucher LJ, Crawford A, Hatton PV, Russell RG, Buttle DJ (2000) Extracellular ATP and UTP stimulate cartilage proteoglycan and collagen accumulation in bovine articular chondrocyte pellet cultures. Biochim Biophys Acta 1502:297–306PubMedGoogle Scholar
  315. 315.
    McVey GF, Crawford A, Smith TW, Buttle DJ (2006) Nucleotide triphosphates enhance collagen II and proteoglycan levels in cartilage without stimulating mRNA levels: potential for purinergic inhibition of matrix degradation pathways? Int J Exp Pathol 87:A37–A38Google Scholar
  316. 316.
    Chowdhury TT, Knight MM (2006) Purinergic pathway suppresses the release of NO and stimulates proteoglycan synthesis in chondrocyte/agarose constructs subjected to dynamic compression. J Cell Physiol 209:845–853PubMedGoogle Scholar
  317. 317.
    Pingguan-Murphy B, El-Azzeh M, Bader DL, Knight MM (2006) Cyclic compression of chondrocytes modulates a purinergic calcium signalling pathway in a strain rate- and frequency-dependent manner. J Cell Physiol 209:389–397PubMedGoogle Scholar
  318. 318.
    Leong WS, Russell RG, Caswell AM (1993) Induction of enhanced responsiveness of human articular chondrocytes to extracellular ATP by tumour necrosis factor-alpha. Clin Sci (Lond) 85:569–575Google Scholar
  319. 319.
    Leong WS, Russell RG, Caswell AM (1994) Stimulation of cartilage resorption by extracellular ATP acting at P2-purinoceptors. Biochim Biophys Acta 1201:298–304PubMedGoogle Scholar
  320. 320.
    Fodor J, Matta C, Juhász T, Oláh T, Gönczi M, Szíjgyártó Z, Gergely P, Csernoch L, Zákány R (2009) Ionotropic purinergic receptor P2X4 is involved in the regulation of chondrogenesis in chicken micromass cell cultures. Cell Calcium 45:421–430PubMedGoogle Scholar
  321. 321.
    Kwon HJ (2012) Extracellular ATP signaling via P2X4 receptor and cAMP/PKA signaling mediate ATP oscillations essential for prechondrogenic condensation. J Endocrinol 214:337–348PubMedGoogle Scholar
  322. 322.
    Kwon HJ (2013) ATP oscillations mediate inductive action of FGF and Shh signalling on prechondrogenic condensation. Cell Biochem Funct 31:75–81PubMedGoogle Scholar
  323. 323.
    Kumahashi N, Ochi M, Kataoka H, Uchio Y, Kakimaru H, Sugawara K, Enomoto K (2004) Involvement of ATP, increase of intracellular calcium and the early expression of c-fos in the repair of rat fetal articular cartilage. Cell Tissue Res 317:117–128PubMedGoogle Scholar
  324. 324.
    Waldman SD, Usprech J, Flynn LE, Khan AA (2010) Harnessing the purinergic receptor pathway to develop functional engineered cartilage constructs. Osteoarth Cart 18:864–872Google Scholar
  325. 325.
    Graff RD, Lazarowski ER, Banes AJ, Lee GM (2000) ATP release by mechanically loaded porcine chondrons in pellet culture. Arthritis Rheum 43:1571–1579PubMedGoogle Scholar
  326. 326.
    Graff RD, Picher M, Lee GM (2003) Extracellular nucleotides, cartilage stress, and calcium crystal formation. Curr Opin Rheumatol 15:315–320PubMedGoogle Scholar
  327. 327.
    Mason HS, Wright MO, Hall AC, Macdonald AG (1998) The effect of hypotonically induced stretch on the ion channel activity of cultured human articular chondrocytes. J Physiol 507:20PGoogle Scholar
  328. 328.
    Yellowley CE, Jacobs CR, Donahue HJ (1999) Mechanisms contributing to fluid-flow-induced Ca2+ mobilization in articular chondrocytes. J Cell Physiol 180:402–408PubMedGoogle Scholar
  329. 329.
    Millward-Sadler SJ, Wright MO, Flatman PW, Salter DM (2004) ATP in the mechanotransduction pathway of normal human chondrocytes. Biorheology 41:567–575PubMedGoogle Scholar
  330. 330.
    Dillon JP, Vindigni G, Collins J, Wilson PJ, Ranganath LR, Milner PI, Gallagher JA (2013) ATP-stimulated ATP release and metabolic acid production-regulating life and death decisions in articular chondrocytes. Osteoarth Cart 21:S111Google Scholar
  331. 331.
    Wann AK, Zuo N, Haycraft CJ, Jensen CG, Poole CA, McGlashan SR, Knight MM (2012) Primary cilia mediate mechanotransduction through control of ATP-induced Ca2+ signaling in compressed chondrocytes. FASEB J 26:1663–1671PubMedPubMedCentralGoogle Scholar
  332. 332.
    Garcia M, Knight MM (2010) Cyclic loading opens hemichannels to release ATP as part of a chondrocyte mechanotransduction pathway. J Orthop Res 28:510–515PubMedGoogle Scholar
  333. 333.
    Iwamoto T, Nakamura T, Doyle A, Ishikawa M, de Vega S, Fukumoto S, Yamada Y (2010) Pannexin 3 regulates intracellular ATP/cAMP levels and promotes chondrocyte differentiation. J Biol Chem 285:18948–18958PubMedPubMedCentralGoogle Scholar
  334. 334.
    Kanabe S, Hsu HH, Cecil RN, Anderson HC (1983) Electron microscopic localization of adenosine triphosphate (ATP)-hydrolyzing activity in isolated matrix vesicles and reconstituted vesicles from calf cartilage. J Histochem Cytochem 31:462–470PubMedGoogle Scholar
  335. 335.
    Rosenthal AK, Hempel D, Kurup IV, Masuda I, Ryan LM (2010) Purine receptors modulate chondrocyte extracellular inorganic pyrophosphate production. Osteoarth Cart 18:1496–1501Google Scholar
  336. 336.
    Yamakawa H (1999) Induction of chondrocyte apoptosis by adenosine. Ehime Med J 18:220–232Google Scholar
  337. 337.
    Tesch AM, MacDonald MH, Kollias-Baker C, Benton HP (2002) Chondrocytes respond to adenosine via A2 receptors and activity is potentiated by an adenosine deaminase inhibitor and a phosphodiesterase inhibitor. Osteoarth Cart 10:34–43Google Scholar
  338. 338.
    Varani K, De Mattei M, Vincenzi F, Gessi S, Merighi S, Pellati A, Ongaro A, Caruso A, Cadossi R, Borea PA (2008) Characterization of adenosine receptors in bovine chondrocytes and fibroblast-like synoviocytes exposed to low frequency low energy pulsed electromagnetic fields. Osteoarth Cart 16:292–304Google Scholar
  339. 339.
    Campo GM, Avenoso A, D'Ascola A, Scuruchi M, Prestipino V, Nastasi G, Calatroni A, Campo S (2012) Adenosine A2A receptor activation and hyaluronan fragment inhibition reduce inflammation in mouse articular chondrocytes stimulated with interleukin-1β. FEBS J 279:2120–2133PubMedGoogle Scholar
  340. 340.
    Luckprom P, Wongkhantee S, Yongchaitrakul T, Pavasant P (2010) Adenosine triphosphate stimulates RANKL expression through P2Y1 receptor-cyclo-oxygenase-dependent pathway in human periodontal ligament cells. J Periodontal Res 45:404–411PubMedGoogle Scholar
  341. 341.
    Wongkhantee S, Yongchaitrakul T, Pavasant P (2007) Mechanical stress induces osteopontin expression in human periodontal ligament cells through rho kinase. J Periodontol 78:1113–1119PubMedGoogle Scholar
  342. 342.
    Pavasant P, Yongchaitrakul T (2001) Role of mechanical stress on the function of periodontal ligament cells. Periodontol 56:154–165Google Scholar
  343. 343.
    Luckprom P, Kanjanamekanant K, Pavasant P (2011) Role of connexin43 hemichannels in mechanical stress-induced ATP release in human periodontal ligament cells. J Periodontal Res 46:607–615PubMedGoogle Scholar
  344. 344.
    Kanjanamekanant K, Luckprom P, Pavasant P (2013) Mechanical stress-induced interleukin-1beta expression through adenosine triphosphate/P2X7 receptor activation in human periodontal ligament cells. J Periodontal Res 48:169–176PubMedGoogle Scholar
  345. 345.
    Franckel E, Sood A, Kenamond C, Yang X, Faber J, Boitano S, Bynum D, Yang X, Sanderson M, Barnes A (1997) Human tendon cells express purinergic receptors temporally blocked by ATP in a mechanical load response. Mol Biol Cell 8:416aGoogle Scholar
  346. 346.
    Tsuzaki M, Bynum D, Almekinders L, Yang X, Faber J, Banes AJ (2003) ATP modulates load-inducible IL-1β, COX 2, and MMP-3 gene expression in human tendon cells. J Cell Biochem 89:556–562PubMedGoogle Scholar
  347. 347.
    Tsuzaki M, Bynum D, Almekinders L, Faber J, Banes AJ (2005) Mechanical loading stimulates ecto-ATPase activity in human tendon cells. J Cell Biochem 96:117–125PubMedGoogle Scholar
  348. 348.
    Kindig AE, Hayes SG, Hanna RL, Kaufman MP (2006) P2 antagonist PPADS attenuates responses of thin fiber afferents to static contraction and tendon stretch. Am J Physiol Heart Circ Physiol 290:H1214–H1219PubMedGoogle Scholar
  349. 349.
    Yu KT, Gould MK (1978) Permissive effect of ATP on insulin-stimulated sugar transport by rat soleus muscle. Am J Physiol 234:E407–E416PubMedGoogle Scholar
  350. 350.
    Nordenberg J, Beery E, Klein S, Kaplansky M, Frucht H, Beitner R (1987) Exogenous ATP antagonizes the actions of phospholipase A2, local anesthetics, Ca2+ ionophore A23187, and lithium on glucose-1,6-bisphosphate levels and the activities of phosphofructokinase and phosphoglucomutase in rat muscle. Biochem Med Metab Biol 38:278–291PubMedGoogle Scholar
  351. 351.
    Bertorini TE, Palmieri GM, Griffin J, Chesney C, Pifer D, Verling L, Airozo D, Fox IH (1985) Chronic allopurinol and adenine therapy in Duchenne muscular dystrophy: effects on muscle function, nucleotide degradation, and muscle ATP and ADP content. Neurology 35:61–65PubMedGoogle Scholar
  352. 352.
    Ferrari D, Munerati M, Melchiorri L, Hanau S, Di Virgilio F, Baricordi OR (1994) Responses to extracellular ATP of lymphoblastoid cell lines from Duchenne muscular dystrophy patients. Am J Physiol 267:C886–C892PubMedGoogle Scholar
  353. 353.
    Betto R, Senter L, Ceoldo S, Tarricone E, Biral D, Salviati G (1999) Ecto-ATPase activity of α-sarcoglycan (adhalin). J Biol Chem 274:7907–7912PubMedGoogle Scholar
  354. 354.
    Ryten M, Yang SY, Dunn PM, Goldspink G, Burnstock G (2004) urinoceptor expression in regenerating skeletal muscle in the mdx mouse model of muscular dystrophy and in satellite cell cultures. FASEB J 18:1404–1406, (printed version) [Full version online (Epub, 2004, July 1, 34 pages)]PubMedGoogle Scholar
  355. 355.
    Yeung D, Zablocki K, Lien CF, Jiang T, Arkle S, Brutkowski W, Brown J, Lochmuller H, Simon J, Barnard EA, Górecki DC (2006) Increased susceptibility to ATP via alteration of P2X receptor function in dystrophic mdx mouse muscle cells. FASEB J 20:610–620PubMedGoogle Scholar
  356. 356.
    Kennedy C, Leff P (1995) How should P2X purinoceptors be classified pharmacologically? Trends Pharmacol Sci 16:168–174PubMedGoogle Scholar
  357. 357.
    Bland-Ward PA, Humphrey PPA (1997) Acute nociception mediated by hindpaw P2X receptor activation in the rat. Br J Pharmacol 122:365–371PubMedPubMedCentralGoogle Scholar
  358. 358.
    Mork H, Ashina M, Bendtsen L, Olesen J, Jensen R (2003) Experimental muscle pain and tenderness following infusion of endogenous substances in humans. Eur J Pain 7:145–153PubMedGoogle Scholar
  359. 359.
    Young CN, Brutkowski W, Lien CF, Arkle S, Lochmüller H, Zablocki K, Górecki DC (2012) P2X7 purinoceptor alterations in dystrophic mdx mouse muscles: relationship to pathology and potential target for treatment. J Cell Mol Med 16:1026–1037PubMedGoogle Scholar
  360. 360.
    Valladares D, Casas M, Figueroa R, Leyton A, Buvinic S, Jaimovich E (2011) ATP sensitivity and IP3-dependent calcium transients which regulate gene expression in adult muscle fibres are altered in Mdx mice. Biophys J 100:592aGoogle Scholar
  361. 361.
    Valladares D, Almarza G, Pavez M, Jaimovich E (2012) ATP release is altered in a mouse model for Duchenne muscular dystrophy and signals for proteins that promote cell death. FASEB J 26:798.23Google Scholar
  362. 362.
    Noronha-Matos JB, Morais T, Trigo D, Timóteo MA, Magalhães-Cardoso MT, Oliveira L, Correia-de-Sá P (2011) Tetanic failure due to decreased endogenous adenosine A2A tonus operating neuronal Cav 1 (L-type) influx in Myasthenia gravis. J Neurochem 117:797–811PubMedGoogle Scholar
  363. 363.
    Bazzichi L, Giannaccini G, Betti L, Fabbrini L, Schmid L, Palego L, Giacomelli C, Rossi A, Giusti L, De Feo F, Giuliano T, Mascia G, Bombardieri S, Lucacchini A (2008) ATP, calcium and magnesium levels in platelets of patients with primary fibromyalgia. Clin Biochem 41:1084–1090PubMedGoogle Scholar
  364. 364.
    Chidsey-Frink KL, Qi H, Crawford DT, Simmons HA, Audoly LP, Gabel CA, Thompson DD, Ke H (2001) Decreased cancellous and cortical bone mass in female mice lacking the P2X7 receptor. J Bone Miner Res 16:S378Google Scholar
  365. 365.
    Bours MJ, Jørgensen NR, van Helden S, van Rhijn L, Geusens P, Wesselius A, Dagnelie PC (2008) Contributors to secondary osteoporosis and metabolic bone diseases in patients presenting with a clinical fracture. Purinergic Signal 4:S171Google Scholar
  366. 366.
    Agrawal A, Buckley KA, Bowers K, Furber M, Gallagher JA, Gartland A (2010) The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro. Purinergic Signal 6:307–315PubMedPubMedCentralGoogle Scholar
  367. 367.
    Jørgensen NR, Boeynaems JM, Di Virgilio F (2011) European meeting "P2 receptors: new targets for the treatment of osteoporosis". Purinergic Signal 7:275–276PubMedPubMedCentralGoogle Scholar
  368. 368.
    Wesselius A, Bours MJ, Jørgensen NR, Wiley J, Gu B, van Helden S, van Rhijn L, Dagnelie PC (2013) Non-synonymous polymorphisms in the P2RX 4 are related to bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients. Purinergic Signal 9:123–130PubMedPubMedCentralGoogle Scholar
  369. 369.
    McPhee MD, Whiting SJ (1989) The effect of adenosine and adenosine analogues on methylxanthine-induced hypercalciuria in the rat. Can J Physiol Pharmacol 67:1278–1282PubMedGoogle Scholar
  370. 370.
    Kara FM, Doty SB, Boskey A, Fredholm BB, Cronstein BN (2007) Adenosine and osteoporosis: adenosine A1 receptor blockade reverses bone loss in ovariectomized mice and deletion of adenosine A2A receptors leads to diminished bone density. J Bone Min Res 22:S36Google Scholar
  371. 371.
    Kara FM, Axelrod M, Sloane J, Doty SB, Boskey A, Cronstein BN (2008) Adenosine and osteoporosis: adenosine A2A and A2B receptor blockade or deletion leads to diminished bone density. Presented at the American College of Rheumatology Scientific Meeting, San Francisco, October 24–29, 2008Google Scholar
  372. 372.
    Gharibi B, Ham J, Evans BA (2010) Adenosine A2b receptors induce osteoblastogenesis whereas A1 receptors induce adipogenesis. Bone 46:S48–S49Google Scholar
  373. 373.
    Rayalam S, Yang JY, la-Fera MA, Baile CA (2011) Novel molecular targets for prevention of obesity and osteoporosis. J Nutr Biochem 22:1099–1104PubMedGoogle Scholar
  374. 374.
    Niikura K (2006) Comparative analysis of the effects of a novel vacuolar adenosine 5′-triphosphatase inhibitor, FR202126, and doxycycline on bone loss caused by experimental periodontitis in rats. J Periodontol 77:1211–1216PubMedGoogle Scholar
  375. 375.
    Mönkkönen H, Auriola S, Lehenkari P, Kellinsalmi M, Hassinen IE, Vepsäläinen J, Mönkkönen J (2006) A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147:437–445PubMedPubMedCentralGoogle Scholar
  376. 376.
    Hong KC, Cruess RL (1978) Changes in organic matrix of bone and of bone and blood ATP in rats fed rachitogenic diets. Calcif Tissue Res 25:241–244PubMedGoogle Scholar
  377. 377.
    Sawada T, Kishiya M, Kanemaru K, Seya K, Yokoyama T, Ueyama K, Motomura S, Toh S, Furukawa K (2008) Possible role of extracellular nucleotides in ectopic ossification of human spinal ligaments. J Pharmacol Sci 106:152–161PubMedGoogle Scholar
  378. 378.
    Tanaka S, Kudo H, Asari T, Ono A, Motomura S, Toh S, Furukawa K (2011) P2Y1 transient overexpression induced mineralization in spinal ligament cells derived from patients with ossification of the posterior longitudinal ligament of the cervical spine. Calcif Tissue Int 88:263–271PubMedGoogle Scholar
  379. 379.
    Herbert KE, Bhusate LL, Scott DL, Perrett D (1991) Purine metabolism in arthritis: 1. synovial fluid adenosine concentrations are low in rheumatoid arthritis. Int J Purine Pysimidine Res 2:31–34Google Scholar
  380. 380.
    Ryan LM, Rachow JW, McCarty DJ (1991) Synovial fluid ATP: a potential substrate for the production of inorganic pyrophosphate. J Rheumatol 18:716–720PubMedGoogle Scholar
  381. 381.
    Wortmann RL, Veum JA, Rachow JW (1991) Synovial fluid 5′-nucleotidase activity. Relationship to other purine catabolic enzymes and to arthropathies associated with calcium crystal deposition. Arthritis Rheum 34:1014–1020PubMedGoogle Scholar
  382. 382.
    Loredo GA, Benton HP (1998) ATP and UTP activate calcium-mobilizing P2U-like receptors and act synergistically with interleukin-1 to stimulate prostaglandin E2 release from human rheumatoid synovial cells. Arthritis Rheum 41:246–255PubMedGoogle Scholar
  383. 383.
    Al-Shukaili A, Al-Kaabi J, Hassan B (2008) A comparative study of interleukin-1β production and P2X7 expression after Atp stimulation by peripheral blood mononuclear cells isolated from rheumatoid arthritis patients and normal healthy controls. Inflammation 31:84–90PubMedGoogle Scholar
  384. 384.
    Portales-Cervantes L, Niño-Moreno P, Doníz-Padilla L, Baranda-Candido L, García-Hernández M, Salgado-Bustamante M, González-Amaro R, Portales-Pérez D (2010) Expression and function of the P2X7 purinergic receptor in patients with systemic lupus erythematosus and rheumatoid arthritis. Hum Immunol 71:818–825PubMedGoogle Scholar
  385. 385.
    Portales-Cervantes L, Niño-Moreno P, Salgado-Bustamante M, García-Hernández MH, Baranda-Candido L, Reynaga-Hernández E, Barajas-López C, González-Amaro R, Portales-Pérez DP (2012) The His155Tyr (489C>T) single nucleotide polymorphism of P2RX7 gene confers an enhanced function of P2X7 receptor in immune cells from patients with rheumatoid arthritis. Cell Immunol 276:168–175PubMedGoogle Scholar
  386. 386.
    Caporali F, Capecchi PL, Gamberucci A, Lazzerini PE, Pompella G, Natale M, Lorenzini S, Selvi E, Galeazzi M, Laghi PF (2008) Human rheumatoid synoviocytes express functional P2X7 receptors. J Mol Med (Berl) 86:937–949Google Scholar
  387. 387.
    Gavala ML, Hill LM, Lenertz LY, Karta MR, Bertics PJ (2010) Activation of the transcription factor FosB/activating protein-1 (AP-1) is a prominent downstream signal of the extracellular nucleotide receptor P2RX7 in monocytic and osteoblastic cells. J Biol Chem 285:34288–34298PubMedPubMedCentralGoogle Scholar
  388. 388.
    Labasi JM, Petrushova N, Donovan C, McCurdy S, Lira P, Payette MM, Brissette W, Wicks JR, Audoly L, Gabel CA (2002) Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol 168:6436–6445PubMedGoogle Scholar
  389. 389.
    Ardissone V, Radaelli E, Zaratin P, Ardizzone M, Ladel C, Gattorno M, Martini A, Grassi F, Traggiai E (2011) Pharmacologic P2X purinergic receptor antagonism in the treatment of collagen-induced arthritis. Arthritis Rheum 63:3323–3332PubMedGoogle Scholar
  390. 390.
    Keystone EC, Wang MM, Layton M, Hollis S, McInnes IB (2012) Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis 71:1630–1635PubMedGoogle Scholar
  391. 391.
    Beswick PJ, Billinton A, Chambers LJ, Dean DK, Fonfria E, Gleave RJ, Medhurst SJ, Michel AD, Moses AP, Patel S, Roman SA, Roomans S, Senger S, Stevens AJ, Walter DS (2010) Structure-activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor. Bioorg Med Chem Lett 20:4653–4656PubMedGoogle Scholar
  392. 392.
    Bours MJ, Peeters RH, Landewé RB, Dagnelie PC (2008) ATP infusion therapy in patient with rheumatoid arthritis: design of a multicentre double-blind placebo-controlled RCT. Purinergic Signal 4:S180Google Scholar
  393. 393.
    Bours MJ, Peeters RH, Landewé RB, Beijer S, Arts IC, Dagnelie PC (2010) Adenosine 5′-triphosphate infusions reduced disease activity and inflammation in a patient with active rheumatoid arthritis. Rheumatology (Oxford) 49:2223–2225Google Scholar
  394. 394.
    Mac Mullan PA, Peace AJ, Madigan AM, Tedesco AF, Kenny D, McCarthy GM (2010) Platelet hyper-reactivity in active inflammatory arthritis is unique to the adenosine diphosphate pathway: a novel finding and potential therapeutic target. Rheumatology (Oxford) 49:240–245Google Scholar
  395. 395.
    Straub RH, Rauch L, Fassold A, Lowin T, Pongratz G (2008) Neuronally released sympathetic neurotransmitters stimulate splenic interferon-γ secretion from T cells in early type II collagen-induced arthritis. Arthritis Rheum 58:3450–3460PubMedGoogle Scholar
  396. 396.
    Dowd E, McQueen DS, Chessell IP, Humphrey PP (1998) P2X receptor-mediated excitation of nociceptive afferents in the normal and arthritic rat knee joint. Br J Pharmacol 125:341–346PubMedPubMedCentralGoogle Scholar
  397. 397.
    Ishikawa T, Miyagi M, Ohtori S, Aoki Y, Ozawa T, Doya H, Saito T, Moriya H, Takahashi K (2005) Characteristics of sensory DRG neurons innervating the lumbar facet joints in rats. Eur Spine J 14:559–564PubMedPubMedCentralGoogle Scholar
  398. 398.
    Averill S, Inglis JJ, King VR, Thompson SW, Cafferty WB, Shortland PJ, Hunt SP, Kidd BL, Priestley JV (2008) Reg-2 expression in dorsal root ganglion neurons after adjuvant-induced monoarthritis. Neuroscience 155:1227–1236PubMedGoogle Scholar
  399. 399.
    Shinoda M, Ozaki N, Asai H, Nagamine K, Sugiura Y (2005) Changes in P2X3 receptor expression in the trigeminal ganglion following monoarthritis of the temporomandibular joint in rats. Pain 116:42–51PubMedGoogle Scholar
  400. 400.
    Burnstock G (2008) Non-synaptic transmission at autonomic neuroeffector junctions. Neurochem Int 52:14–25PubMedGoogle Scholar
  401. 401.
    Green PG, Luo J, Heller P, Levine JD (1993) Modulation of bradykinin-induced plasma extravasation in the rat knee joint by sympathetic co-transmitters. Neuroscience 52:451–458PubMedGoogle Scholar
  402. 402.
    Levine JD, Fye K, Heller P, Basbaum AI, Whiting-O'Keefe Q (1986) Clinical response to regional intravenous guanethidine in patients with rheumatoid arthritis. J Rheumatol 13:1040–1043PubMedGoogle Scholar
  403. 403.
    Pettersson T, Klockars M, Weber TH, von Essen R (1988) Adenosine deaminase activity in joint effusions. Scand J Rheumatol 17:365–369PubMedGoogle Scholar
  404. 404.
    Yuksel H, Akoglu TF (1988) Serum and synovial fluid adenosine deaminase activity in patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann Rheum Dis 47:492–495PubMedPubMedCentralGoogle Scholar
  405. 405.
    Nakamachi Y, Koshiba M, Nakazawa T, Hatachi S, Saura R, Kurosaka M, Kusaka H, Kumagai S (2003) Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fibroblasts. Arthritis Rheum 48:668–674PubMedGoogle Scholar
  406. 406.
    Zamani B, Jamali R, Jamali A (2012) Serum adenosine deaminase may predict disease activity in rheumatoid arthritis. Rheumatol Int 32:1967–1975PubMedGoogle Scholar
  407. 407.
    Akimoto M, Yunoue S, Otsubo H, Yoshitama T, Kodama K, Matsushita K, Suruga Y, Kozako T, Toji S, Hashimoto S, Uozumi K, Matsuda T, Arima N (2013) Assessment of peripheral blood CD4+ adenosine triphosphate activity in patients with rheumatoid arthritis. Mod Rheumatol 23:19–27PubMedGoogle Scholar
  408. 408.
    Masahiro K, Nakamachi Y, Kosaka H, Nakazawa T, Tsuji G, Kumagai S (2002) 2-Chloroadenosine but adenosine induced apoptosis in rheumatoid fibroblasts independently of adenosine receptor signalling. Drug Dev Res 56:74Google Scholar
  409. 409.
    Masahiro K, Nakamachi Y, Kosaka H, Nakazawa T, Tsuji G, Kumagai S (2003) Modification of cytokine milieu in rheumatoid arthritis by signalling through A2A adenosine receptors. FASEB J 17:C69Google Scholar
  410. 410.
    Forrest CM, Harman G, McMillan RB, Stoy N, Stone TW, Darlington LG (2005) Modulation of cytokine release by purine receptors in patients with rheumatoid arthritis. Clin Exp Rheumatol 23:89–92PubMedGoogle Scholar
  411. 411.
    Forrest CM, Stoy N, Stone TW, Harman G, Mackay GM, Oxford L, Darlington LG (2006) Adenosine and cytokine levels following treatment of rheumatoid arthritis with dipyridamole. Rheumatol Int 27:11–17PubMedGoogle Scholar
  412. 412.
    Madi L, Cohen S, Ochayin A, Bar-Yehuda S, Barer F, Fishman P (2007) Overexpression of A3 adenosine receptor in peripheral blood mononuclear cells in rheumatoid arthritis: involvement of nuclear factor-κB in mediating receptor level. J Rheumatol 34:20–26PubMedGoogle Scholar
  413. 413.
    Stamp LK, Hazlett J, Roberts RL, Frampton C, Highton J, Hessian PA (2012) Adenosine receptor expression in rheumatoid synovium: a basis for methotrexate action. Arthritis Res Ther 14:R138PubMedPubMedCentralGoogle Scholar
  414. 414.
    Varani K, Massara A, Vincenzi F, Tosi A, Padovan M, Trotta F, Borea PA (2009) Normalization of A2A and A3 adenosine receptor up-regulation in rheumatoid arthritis patients by treatment with anti-tumor necrosis factor alpha but not methotrexate. Arthritis Rheum 60:2880–2891PubMedGoogle Scholar
  415. 415.
    Boyle DL, Moore J, Yang L, Sorkin LS, Firestein GS (2002) Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant-induced arthritis. Arthritis Rheum 46:3076–3082PubMedGoogle Scholar
  416. 416.
    Sorkin LS, Maruyama K, Boyle DL, Yang L, Marsala M, Firestein GS (2003) Spinal adenosine agonist reduces c-fos and astrocyte activation in dorsal horn of rats with adjuvant-induced arthritis. Neurosci Lett 340:119–122PubMedGoogle Scholar
  417. 417.
    Rath-Wolfson L, Bar-Yehuda S, Madi L, Ochaion A, Cohen S, Zabutti A, Fishman P (2006) IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis. Clin Exp Rheumatol 24:400–406PubMedGoogle Scholar
  418. 418.
    Green PG, Basbaum AI, Helms C, Levine JD (1991) Purinergic regulation of bradykinin-induced plasma extravasation and adjuvant-induced arthritis in the rat. Proc Natl Acad Sci USA 88:4162–4165PubMedPubMedCentralGoogle Scholar
  419. 419.
    Ochaion A, Bar-Yehuda S, Cohen S, Amital H, Jacobson KA, Joshi BV, Gao ZG, Barer F, Patoka R, Del Valle L, Perez-Liz G, Fishman P (2008) The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF- signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats. Biochem Pharmacol 76:482–494PubMedPubMedCentralGoogle Scholar
  420. 420.
    Kosaka H, Koshiba M, Nakazawa T, Tsuji G, Saegusa J, Kanagawa S, Saura R, Kurosaka M, Yoshino S, Kumagai S (2003) Inhibition of the nucleoside transporter inhibits disease progression in the rat adjuvant-induced arthritis model. Drug Dev Res 58:479–485Google Scholar
  421. 421.
    Baharav E, Dubrosin A, Fishman P, Bar-Yehuda S, Halpren M, Weinberger A (2002) Suppression of experimental zymosan-induced arthritis by intraperitoneal administration of adenosine. Drug Dev Res 57:182–186Google Scholar
  422. 422.
    Bar-Yehuda S, Silverman MH, Kerns WD, Ochaion A, Cohen S, Fishman P (2007) The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin Investig Drugs 16:1601–1613PubMedGoogle Scholar
  423. 423.
    Fishman P, Ochaion A, Cohen S, Patoka R, Barer F, Bar-Yehuda S (2008) The anti-inflammatory effect of A3 adenosine receptor agonists: a novel target therapy for rheumatoid arthritis. Purinergic Signal 4:S60Google Scholar
  424. 424.
    Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P (2008) Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial. J Rheumatol 35:41–48PubMedGoogle Scholar
  425. 425.
    Mazzon E, Esposito E, Impellizzeri D, Di Paola R, Melani A, Bramanti P, Pedata F, Cuzzocrea S (2011) CGS 21680, an agonist of the adenosine (A2A) receptor, reduces progression of murine type II collagen-induced arthritis. J Rheumatol 38:2119–2129PubMedGoogle Scholar
  426. 426.
    Flögel U, Burghoff S, van Lent PL, Temme S, Galbarz L, Ding Z, El-Tayeb A, Huels S, Bönner F, Borg N, Jacoby C, Müller CE, van den Berg WB, Schrader J (2012) Selective activation of adenosine A2A receptors on immune cells by a CD73-dependent prodrug suppresses joint inflammation in experimental rheumatoid arthritis. Sci Transl Med 4:146ra108PubMedGoogle Scholar
  427. 427.
    Schrader J, Flögel U, Burghoff S, Temme S, Müller CE, El-Tayeb A, van Lent P, Huels S, Bönner F, Borg N, Galbarz L (2012) The anti-inflammatory activity of a phosphorylated adenosine A2A receptor agonist (prodrug) in collagen-induced arthritis. Purinergic Signal 8:121Google Scholar
  428. 428.
    Vincenzi F, Padovan M, Targa M, Corciulo C, Giacuzzo S, Merighi S, Gessi S, Govoni M, Borea PA, Varani K (2013) A2A adenosine receptors are differentially modulated by pharmacological treatments in rheumatoid arthritis patients and their stimulation ameliorates adjuvant-induced arthritis in rats. PLoS One 8:e54195PubMedPubMedCentralGoogle Scholar
  429. 429.
    Ralph JA, McEvoy AN, Kane D, Bresnihan B, FitzGerald O, Murphy EP (2005) Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. J Immunol 175:555–565PubMedGoogle Scholar
  430. 430.
    Teramachi J, Kukita A, Li YJ, Ushijima Y, Ohkuma H, Wada N, Watanabe T, Nakamura S, Kukita T (2011) Adenosine abolishes MTX-induced suppression of osteoclastogenesis and inflammatory bone destruction in adjuvant-induced arthritis. Lab Invest 91:719–731PubMedGoogle Scholar
  431. 431.
    Dervieux T, Wessels JA, van der Straaten T, Penrod N, Moore JH, Guchelaar HJ, Kremer JM (2009) Gene-gene interactions in folate and adenosine biosynthesis pathways affect methotrexate efficacy and tolerability in rheumatoid arthritis. Pharmacogenet Genomics 19:935–944PubMedGoogle Scholar
  432. 432.
    Wessels JA, Kooloos WM, de Jonge R, De Vries-Bouwstra JK, Allaart CF, Linssen A, Collee G, De Sonnaville P, Lindemans J, Huizinga TW, Guchelaar HJ (2006) Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 54:2830–2839PubMedGoogle Scholar
  433. 433.
    Erer B, Yilmaz G, Yilmaz FM, Koklu S (2009) Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF-alpha therapy. Rheumatol Int 29:651–654PubMedGoogle Scholar
  434. 434.
    Zakeri Z, Izadi S, Niazi A, Bari Z, Zendeboodi S, Shakiba M, Mashhadi M, Narouie B, Ghasemi-Rad M (2012) Comparison of adenosine deaminase levels in serum and synovial fluid between patients with rheumatoid arthritis and osteoarthritis. Int J Clin Exp Med 5:195–200PubMedPubMedCentralGoogle Scholar
  435. 435.
    Johnson K, Svensson CI, Etten DV, Ghosh SS, Murphy AN, Powell HC, Terkeltaub R (2004) Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs. Arthritis Rheum 50:1216–1225PubMedGoogle Scholar
  436. 436.
    Costello JC, Rosenthal AK, Kurup IV, Masuda I, Medhora M, Ryan LM (2011) Parallel regulation of extracellular ATP and inorganic pyrophosphate: roles of growth factors, transduction modulators, and ANK. Connect Tissue Res 52:139–146PubMedGoogle Scholar
  437. 437.
    Kumahashi N, Naitou K, Nishi H, Oae K, Watanabe Y, Kuwata S, Ochi M, Ikeda M, Uchio Y (2011) Correlation of changes in pain intensity with synovial fluid adenosine triphosphate levels after treatment of patients with osteoarthritis of the knee with high-molecular-weight hyaluronic acid. Knee 18:160–164PubMedGoogle Scholar
  438. 438.
    Mrazek F, Gallo J, Stahelova A, Petrek M (2010) Functional variants of the P2RX7 gene, aseptic osteolysis, and revision of the total hip arthroplasty: a preliminary study. Hum Immunol 71:201–205PubMedGoogle Scholar
  439. 439.
    Dowd E, McQueen DS, Chessell IP, Humphrey PP (1998) Adenosine A1 receptor-mediated excitation of nociceptive afferents innervating the normal and arthritic rat knee joint. Br J Pharmacol 125:1267–1271PubMedPubMedCentralGoogle Scholar
  440. 440.
    Mistry D, Chambers MG, Mason RM (2006) The role of adenosine in chondrocyte death in murine osteoarthritis and in a murine chondrocyte cell line. Osteoarth Cart 14:486–495Google Scholar
  441. 441.
    Petrov R, MacDonald MH, Tesch AM, Benton HP (2005) Inhibition of adenosine kinase attenuates interleukin-1- and lipopolysaccharide-induced alterations in articular cartilage metabolism. Osteoarth Cart 13:250–257Google Scholar
  442. 442.
    Russell JM, Stephenson GS, Yellowley CE, Benton HP (2007) Adenosine inhibition of lipopolysaccharide-induced interleukin-6 secretion by the osteoblastic cell line MG-63. Calcif Tissue Int 81:316–326PubMedGoogle Scholar
  443. 443.
    De Mattei M, Varani K, Masieri FF, Pellati A, Ongaro A, Fini M, Cadossi R, Vincenzi F, Borea PA, Caruso A (2009) Adenosine analogs and electromagnetic fields inhibit prostaglandin E2 release in bovine synovial fibroblasts. Osteoarth Cart 17:252–262Google Scholar
  444. 444.
    Ongaro A, Varani K, Masieri FF, Pellati A, Massari L, Cadossi R, Vincenzi F, Borea PA, Fini M, Caruso A, De Mattei M (2012) Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E(2) and cytokine release in human osteoarthritic synovial fibroblasts. J Cell Physiol 227:2461–2469PubMedGoogle Scholar
  445. 445.
    Varani K, Vincenzi F, Tosi A, Targa M, Masieri FF, Ongaro A, De Mattei M, Massari L, Borea PA (2010) Expression and functional role of adenosine receptors in regulating inflammatory responses in human synoviocytes. Br J Pharmacol 160:101–115PubMedPubMedCentralGoogle Scholar
  446. 446.
    Cohen SB, Gill SS, Baer GS, Leo BM, Scheld WM, Diduch DR (2004) Reducing joint destruction due to septic arthrosis using an adenosine 2A receptor agonist. J Orthop Res 22:427–435PubMedGoogle Scholar
  447. 447.
    Munoz AM, Frenkel SR, Immerman I, Hadley S, Howell D, Cronstein BN (2010) Adenosine A2A receptor agonists: can they prevent/treat joint prosthesis loosening. Purinergic Signal 6:S159Google Scholar
  448. 448.
    Chirgwin JM, Guise TA (2007) Skeletal metastases: decreasing tumor burden by targeting the bone microenvironment. J Cell Biochem 102:1333–1342PubMedGoogle Scholar
  449. 449.
    Casimiro S, Guise TA, Chirgwin J (2009) The critical role of the bone microenvironment in cancer metastases. Mol Cell Endocrinol 310:71–81PubMedGoogle Scholar
  450. 450.
    Liu PS, Chen CY (2010) Butyl benzyl phthalate suppresses the ATP-induced cell proliferation in human osteosarcoma HOS cells. Toxicol Appl Pharmacol 244:308–314PubMedGoogle Scholar
  451. 451.
    Hatta Y, Aizawa S, Horikoshi A, Baba M, Horie T (1993) Selective killing of murine leukemic cells by adenosine triphosphate (ATP): a study of the value of autologous bone marrow transplantation. Intern Med 32:768–772PubMedGoogle Scholar
  452. 452.
    Uluçkan Ö, Eagleton MC, Floyd DH, Morgan EA, Hirbe AC, Kramer M, Dowland N, Prior JL, Piwnica-Worms D, Jeong SS, Chen R, Weilbaecher K (2008) APT102, a novel ADPase, cooperates with aspirin to disrupt bone metastasis in mice. J Cell Biochem 104:1311–1323PubMedPubMedCentralGoogle Scholar
  453. 453.
    Mönkkönen H, Kuokkanen J, Holen I, Evans A, Lefley DV, Jauhiainen M, Auriola S, Mönkkönen J (2008) Bisphosphonate-induced ATP analog formation and its effect on inhibition of cancer cell growth. Anticancer Drugs 19:391–399PubMedGoogle Scholar
  454. 454.
    Sillero MA, de Diego A, Tavares JE, Silva JA, Pérez-Zúñiga FJ, Sillero A (2009) Synthesis of ATP derivatives of compounds of the mevalonate pathway (isopentenyl di- and triphosphate; geranyl di- and triphosphate, farnesyl di- and triphosphate, and dimethylallyl diphosphate) catalyzed by T4 RNA ligase, T4 DNA ligase and other ligases Potential relationship with the effect of bisphosphonates on osteoclasts. Biochem Pharmacol 78:335–343PubMedGoogle Scholar
  455. 455.
    Park HC, Seong J, An JH, Kim J, Kim UJ, Lee BW (2005) Alteration of cancer pain-related signals by radiation: proteomic analysis in an animal model with cancer bone invasion. Int J Radiat Oncol Biol Phys 61:1523–1534PubMedGoogle Scholar
  456. 456.
    Gilchrist LS, Cain DM, Harding-Rose C, Kov AN, Wendelschafer-Crabb G, Kennedy WR, Simone DA (2005) Re-organization of P2X3 receptor localization on epidermal nerve fibers in a murine model of cancer pain. Brain Res 1044:197–205PubMedGoogle Scholar
  457. 457.
    Kaan TK, Yip PK, Patel S, Davies M, Marchand F, Cockayne DA, Nunn PA, Dickenson AH, Ford AP, Zhong Y, Malcangio M, McMahon SB (2010) Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain 133:2549–2564PubMedGoogle Scholar
  458. 458.
    Hansen RR, Nasser A, Falk S, Baldvinsson SB, Ohlsson PH, Bahl JM, Jarvis MF, Ding M, Heegaard AM (2012) Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice. Eur J Pharmacol 688:27–34PubMedGoogle Scholar
  459. 459.
    Wu JX, Xu MY, Miao XR, Lu ZJ, Yuan XM, Li XQ, Yu WF (2012) Functional up-regulation of P2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain. Eur J Pain 16:1378–1388PubMedGoogle Scholar
  460. 460.
    Hansen RR, Nielsen CK, Nasser A, Thomsen SI, Eghorn LF, Pham Y, Schulenburg C, Syberg S, Ding M, Stojilkovic SS, Jorgensen NR, Heegaard AM (2011) P2X7 receptor-deficient mice are susceptible to bone cancer pain. Pain 152:1766–1776PubMedGoogle Scholar
  461. 461.
    Farrell AW, Gadeock S, Pupovac A, Wang B, Jalilian I, Ranson M, Sluyter R (2010) P2X7 receptor activation induces cell death and CD23 shedding in human RPMI 8226 multiple myeloma cells. Biochim Biophys Acta 1800:1173–1182PubMedGoogle Scholar
  462. 462.
    Chen J, Wang L, Zhang Y, Yang J (2012) P2Y1 purinoceptor inhibition reduces extracellular signal-regulated protein kinase 1/2 phosphorylation in spinal cord and dorsal root ganglia: implications for cancer-induced bone pain. Acta Biochim Biophys Sin (Shanghai) 44:367–372Google Scholar
  463. 463.
    He W, Mazumder A, Cronstein BN (2012) Adenosine regulates bone metabolism via A1, A2A and A2B receptors in bone marrow cells from normal and patients with multiple myeloma. Arthrit Rheumat 64:S833Google Scholar
  464. 464.
    Krett NL, Davies KM, Ayres M, Ma C, Nabhan C, Gandhi V, Rosen ST (2004) 8-amino-adenosine is a potential therapeutic agent for multiple myeloma. Mol Cancer Ther 3:1411–1420PubMedGoogle Scholar
  465. 465.
    Sauer AV, Mrak E, Hernandez RJ, Zacchi E, Cavani F, Casiraghi M, Grunebaum E, Roifman CM, Cervi MC, Ambrosi A, Carlucci F, Roncarolo MG, Villa A, Rubinacci A, Aiuti A (2009) ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood 114:3216–3226PubMedGoogle Scholar
  466. 466.
    Huber C, Oulès B, Bertoli M, Chami M, Fradin M, Alanay Y, Al-Gazali LI, Ausems MG, Bitoun P, Cavalcanti DP, Krebs A, Le Merrer M, Mortier G, Shafeghati Y, Superti-Furga A, Robertson SP, Le Goff C, Muda AO, Paterlini-Bréchot P, Munnich A, Cormier-Daire V (2009) Identification of CANT1 mutations in Desbuquois dysplasia. Am J Hum Genet 85:706–710PubMedPubMedCentralGoogle Scholar
  467. 467.
    Guzmán-Aránguez A, Irazu M, Yayon A, Pintor J (2007) Effect of diadenosine polyphosphates in achondroplasic chondrocytes: inhibitory effect of Ap4A on FGF9 induced MAPK cascade. Biochem Pharmacol 74:448–456PubMedGoogle Scholar
  468. 468.
    Guzmán-Aránguez A, Irazu M, Yayon A, Pintor J (2008) P2Y receptors activated by diadenosine polyphosphates reestablish Ca2+ transients in achondroplasic chondrocytes. Bone 42:516–523PubMedGoogle Scholar
  469. 469.
    Huete F, Guzmán-Aránguez A, Ortin J, Hoyle CH, Pintor J (2011) Effects of diadenosine tetraphosphate on FGF9-induced chloride flux changes in achondroplastic chondrocytes. Purinergic Signal 7:243–249PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Geoffrey Burnstock
    • 1
    • 2
  • Timothy R. Arnett
    • 3
  • Isabel R. Orriss
    • 3
  1. 1.Autonomic Neuroscience CentreUniversity College Medical SchoolLondonUK
  2. 2.Department of PharmacologyThe University of MelbourneMelbourneAustralia
  3. 3.Department of Cell & Developmental BiologyUniversity College LondonLondonUK

Personalised recommendations