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Regulation of bone and cartilage by adenosine signaling

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Abstract

There is growing recognition that bone serves important endocrine and immunologic functions that are compromised in several disease states. While many factors are known to affect bone metabolism, recent attention has focused on investigating the role of purinergic signaling in bone formation and regulation. Adenosine is a purine nucleoside produced intracellularly and extracellularly in response to stimuli such as hypoxia and inflammation, which then interacts with P1 receptors. Numerous studies have suggested that these receptors play a pivotal role in osteoblast, osteoclast, and chondrocyte differentiation and function. This review discusses the various ways by which adenosine signaling contributes to bone and cartilage homeostasis, while incorporating potential therapeutic applications of these signaling pathways.

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References

  1. Fukumoto S, Martin TJ (2009) Bone as an endocrine organ. Trends Endocrinology Metab 20(5):230–236

    Article  CAS  Google Scholar 

  2. Olsen BR, Reginato AM, Wang W (2000) Bone development. Annu Rev Cell Dev Biol 16(1):191–220

    Article  CAS  PubMed  Google Scholar 

  3. Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98(5):1076–1084

    Article  CAS  PubMed  Google Scholar 

  4. Auf’mkolk B, Hauschka PV, Schwartz ER (1985) Characterization of human bone cells in culture. Calcif Tissue Int 37(3):228–235

    Article  PubMed  Google Scholar 

  5. Schwarz M, Harbers K, Kratochwil K (1990) Transcription of a mutant collagen I gene is a cell type and stage-specific marker for odontoblast and osteoblast differentiation. Development 108(4):717–726

    CAS  PubMed  Google Scholar 

  6. Termine JD (1988) Non-collagen proteins in bone. Cell and molecular biology of vertebrate hard tissues:178–190

  7. Turner RT, Colvard DS, Spelsberg TC (1990) Estrogen inhibition of periosteal bone formation in rat long bones: down-regulation of gene expression for bone matrix proteins*. Endocrinology 127(3):1346–1351

    Article  CAS  PubMed  Google Scholar 

  8. Dougall WC (2012) Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin Cancer Res 18(2):326–335

    Article  CAS  PubMed  Google Scholar 

  9. Nelson CA, Warren JT, Wang MWH, Teitelbaum SL, Fremont DH (2012) RANKL employs distinct binding modes to engage RANK and the osteoprotegerin decoy receptor. Structure 20(11):1971–1982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Burgess TL, Y-x Q, Kaufman S, Ring BD, Van G, Capparelli C, Kelley M, Hsu H, Boyle WJ, Dunstan CR (1999) The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol 145(3):527–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hofbauer LC, Schoppet M (2004) Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 292(4):490–495

    Article  CAS  PubMed  Google Scholar 

  12. Augat P, Simon U, Liedert A, Claes L (2005) Mechanics and mechano-biology of fracture healing in normal and osteoporotic bone. Osteoporos Int 16(2):S36–S43

    Article  PubMed  Google Scholar 

  13. Asagiri M, Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40(2):251–264

    Article  CAS  PubMed  Google Scholar 

  14. Jimi E, Shuto T, Koga T (1995) Macrophage colony-stimulating factor and interleukin-1 alpha maintain the survival of osteoclast-like cells. Endocrinology 136(2):808–811

    CAS  PubMed  Google Scholar 

  15. Hoebertz A, Arnett TR, Burnstock G (2003) Regulation of bone resorption and formation by purines and pyrimidines. Trends Pharmacol Sci 24(6):290–297

    Article  CAS  PubMed  Google Scholar 

  16. Drury AN, Av S-G (1929) The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 68(3):213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fredholm BB, Ijzerman AP, Jacobson KA, Linden J, Müller CE (2011) International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors—an update. Pharmacol Rev 63(1):1–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shimegi S (1996) ATP and adenosine act as a mitogen for osteoblast-like cells (MC3T3-E1). Calcif Tissue Int 58(2):109–113

    Article  CAS  PubMed  Google Scholar 

  19. Manson D, Diamond L, Oudjhane K, Hussain FB, Roifman C, Grunebaum E (2013) Characteristic scapular and rib changes on chest radiographs of children with ADA-deficiency SCIDS in the first year of life. Pediatr Radiol 43(5):589–592

    Article  PubMed  Google Scholar 

  20. Sauer AV, Mrak E, Hernandez RJ, Zacchi E, Cavani F, Casiraghi M, Grunebaum E, Roifman CM, Cervi MC, Ambrosi A (2009) ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood 114(15):3216–3226

    Article  CAS  PubMed  Google Scholar 

  21. Evans BAJ, 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(2):228–236

    Article  CAS  PubMed  Google Scholar 

  22. Iser IC, Bracco PA, Gonçalves CEI, Zanin RF, Nardi NB, Lenz G, Battastini AMO, Wink MR (2014) Mesenchymal stem cells from different murine tissues have differential capacity to metabolize extracellular nucleotides. J Cell Biochem 115(10):1673–1682

    Article  CAS  PubMed  Google Scholar 

  23. Burnstock G, Kennedy C (1985) Is there a basis for distinguishing two types of P 2-purinoceptor? Gen Pharmacol 16(5):433–440

    Article  CAS  PubMed  Google Scholar 

  24. Ballarin M, Fredholm BB, Ambrosio S, Mahy N (1991) Extracellular levels of adenosine and its metabolites in the striatum of awake rats: inhibition of uptake and metabolism. Acta Physiol Scand 142(1):97–103

    Article  CAS  PubMed  Google Scholar 

  25. King AE, Ackley MA, Cass CE, Young JD, Baldwin SA (2006) Nucleoside transporters: from scavengers to novel therapeutic targets. Trends Pharmacol Sci 27(8):416–425

    Article  CAS  PubMed  Google Scholar 

  26. Linden J (2005) Adenosine in tissue protection and tissue regeneration. Mol Pharmacol 67(5):1385–1387

    Article  CAS  PubMed  Google Scholar 

  27. Takedachi M, Oohara H, Smith BJ, Iyama M, Kobashi M, Maeda K, Long CL, Humphrey MB, Stoecker BJ, Toyosawa S (2012) CD73‐generated adenosine promotes osteoblast differentiation. J Cell Physiol 227(6):2622–2631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jacobson KA, Gao Z-G (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5(3):247–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461(7261):282–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lazarowski ER (2012) Vesicular and conductive mechanisms of nucleotide release. Purinergic Signalling 8(3):359–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rosenthal AK, Gohr CM, Mitton-Fitzgerald E, Lutz MK, Dubyak GR, Ryan LM (2013) The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes. Arthritis Res Ther 15(5):R154. doi:10.1186/ar4337

    Article  PubMed  PubMed Central  Google Scholar 

  32. 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(1):155–162

    Article  CAS  PubMed  Google Scholar 

  33. Brandao-Burch A, Burnstock G, Arnett TR, Orriss IR (2011) The P2X7 receptor is an important regulator of extracellular ATP levels. Bone 48:S131

    Article  Google Scholar 

  34. MacDonald PE, Braun M, Galvanovskis J, Rorsman P (2006) Release of small transmitters through kiss-and-run fusion pores in rat pancreatic β cells. Cell Metab 4(4):283–290

    Article  CAS  PubMed  Google Scholar 

  35. Zhang Q, Li Y, Tsien RW (2009) The dynamic control of kiss-and-run and vesicular reuse probed with single nanoparticles. Science 323(5920):1448–1453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Young JD, Yao SYM, Sun L, Cass CE, Baldwin SA (2008) Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica 38(7–8):995–1021

    Article  CAS  PubMed  Google Scholar 

  37. Grenz A, Bauerle JD, Dalton JH, Ridyard D, Badulak A, Tak E, McNamee EN, Clambey E, Moldovan R, Reyes G (2012) Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. J Clin Invest 122(2):693–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rose JB, Naydenova Z, Bang A, Ramadan A, Klawitter J, Schram K, Sweeney G, Grenz A, Eltzschig H, Hammond J (2011) Absence of equilibrative nucleoside transporter 1 in ENT1 knockout mice leads to altered nucleoside levels following hypoxic challenge. Life Sci 89(17):621–630

    Article  CAS  PubMed  Google Scholar 

  39. Ii H, Warraich S, Tenn N, Quinonez D, Holdsworth DW, Hammond JR, Dixon SJ, Séguin CA (2016) Disruption of biomineralization pathways in spinal tissues of a mouse model of diffuse idiopathic skeletal hyperostosis. Bone 90:37–49

    Article  CAS  PubMed  Google Scholar 

  40. Warraich S, Bone DBJ, Quinonez D, Ii H, Choi DS, Holdsworth DW, Drangova M, Dixon SJ, Séguin CA, Hammond JR (2013) Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans. J Bone Miner Res 28(5):1135–1149

    Article  CAS  PubMed  Google Scholar 

  41. Daniels G, Ballif BA, Helias V, Saison C, Grimsley S, Mannessier L, Hustinx H, Lee E, Cartron J-P, Peyrard T (2015) Lack of the nucleoside transporter ENT1 results in the Augustine-null blood type and ectopic mineralization. Blood 125(23):3651–3654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hinton DJ, McGee-Lawrence ME, Lee MR, Kwong HK, Westendorf JJ, Choi D-S (2014) Aberrant bone density in aging mice lacking the adenosine transporter ENT1. PLoS One 9(2):e88818

    Article  PubMed  PubMed Central  Google Scholar 

  43. Mishina M, Kimura Y, Naganawa M, Ishii K, Oda K, Sakata M, Toyohara J, Kobayashi S, Katayama Y, Ishiwata K (2012) Differential effects of age on human striatal adenosine A1 and A2A receptors. Synapse 66(9):832–839

    Article  CAS  PubMed  Google Scholar 

  44. Burnstock G (1976) Purinergic receptors. J Theor Biol 62(2):491–503

    Article  CAS  PubMed  Google Scholar 

  45. Tucker AL (1993) Short review cloned receptors and cardiovascular responses to adenosine. Cardiovasc Res 27:62–61

    Article  CAS  PubMed  Google Scholar 

  46. Verzijl D, Ijzerman AP (2011) Functional selectivity of adenosine receptor ligands. Purinergic Signalling 7(2):171–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim S-H, Kim Y-K, Park H-W, Kim S-H, Kim S-H, Ye Y-M, Min K-U, Park H-S (2009) Adenosine deaminase and adenosine receptor polymorphisms in aspirin-intolerant asthma. Respir Med 103(3):356–363

    Article  PubMed  Google Scholar 

  48. Tang Z, Diamond MA, Chen JM, Holly TA, Bonow RO, Dasgupta A, Hyslop T, Purzycki A, Wagner J, McNamara DM (2007) Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy. Clin Pharmacol Ther 82(4):435–440

    Article  CAS  PubMed  Google Scholar 

  49. Hider SL, Thomson W, Mack LF, Armstrong DJ, Shadforth M, Bruce IN (2008) Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in RA patients treated with MTX. Rheumatology 47(8):1156–1159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA (2004) Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacol 29(3):558–565

    Article  CAS  Google Scholar 

  51. 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(7):2325–2333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. He W, Wilder T, Cronstein BN (2013) Rolofylline, an adenosine A1 receptor antagonist, inhibits osteoclast differentiation as an inverse agonist. Br J Pharmacol 170(6):1167–1176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. He W, Cronstein BN (2012) Adenosine A1 receptor regulates osteoclast formation by altering TRAF6/TAK1 signaling. Purinergic Signalling 8(2):327–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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(2):534–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mediero A, Kara FM, Wilder T, Cronstein BN (2012) Adenosine A 2A receptor ligation inhibits osteoclast formation. Am J Pathol 180(2):775–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mediero A, Perez‐Aso M, Cronstein BN (2013) Activation of adenosine A2A receptor reduces osteoclast formation via PKA‐and ERK1/2‐mediated suppression of NFkB nuclear translocation. Br J Pharmacol 169(6):1372–1388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mediero A, Perez-Aso M, Cronstein BN (2013) Activation of adenosine A2A receptor reduces osteoclast formation via PKA- and ERK1/2-mediated suppression of NFkappaB nuclear translocation. Br J Pharmacol 169(6):1372–1388. doi:10.1111/bph.12227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A, Pando MP, Asano T, Verma IM, Oda H (2000) Reciprocal role of ERK and NF-kB pathways in survival and activation of osteoclasts. J Cell Biol 148(2):333–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Saulnier N, Guihard S, Holy X, Decembre E, Jurdic P, Clay D, Feuillet V, Pagès G, Pouysségur J, Porteu F (2012) ERK1 regulates the hematopoietic stem cell niches. PLoS One 7(1):e30788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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(4):1264–1274

    Article  CAS  PubMed  Google Scholar 

  61. 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 4(135):135ra165

    Article  Google Scholar 

  62. Mediero A, Perez‐Aso M, Wilder T, Cronstein BN (2015) Brief report: methotrexate prevents wear particle–induced inflammatory osteolysis in mice via activation of adenosine A2A receptor. Arthritis Rheumatol 67(3):849–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Teramachi J, Kukita A, Li Y-J, 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 Investig 91(5):719–731

    Article  CAS  PubMed  Google Scholar 

  64. Rath-Wolfson L, Bar-Yehuda S, Madi L, Ochaion A, Cohen S, Zabutti A, Fishman P (2006) IB-MECA, an A. Clin Exp Rheumatol 24:400–406

    CAS  PubMed  Google Scholar 

  65. Varani K, Vincenzi F, Targa M, Paradiso B, Parrilli A, Fini M, Lanza G, Borea PA (2013) The stimulation of A3 adenosine receptors reduces bone-residing breast cancer in a rat preclinical model. Eur J Cancer 49(2):482–491

    Article  CAS  PubMed  Google Scholar 

  66. Panjehpour M, Karami-Tehrani F (2007) Adenosine modulates cell growth in the human breast cancer cells via adenosine receptors. Oncol Res 16(12):575–585

    Article  CAS  PubMed  Google Scholar 

  67. Mediero A, Cronstein BN (2013) Adenosine and bone metabolism. Trends Endocrinol Metab 24(6):290–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Carroll SH, Ravid K (2013) Differentiation of mesenchymal stem cells to osteoblasts and chondrocytes: a focus on adenosine receptors. Expert Reviews in Molecular Medicine 15. doi:10.1017/erm.2013.2

  69. Gharibi B, Abraham AA, Ham J, Evans BAJ (2012) Contrasting effects of A1 and A2b adenosine receptors on adipogenesis. Int J Obes 36(3):397–406

    Article  CAS  Google Scholar 

  70. Gharibi B, Abraham AA, Ham J, Evans BAJ (2011) Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. J Bone Miner Res 26(9):2112–2124

    Article  CAS  PubMed  Google Scholar 

  71. D’Alimonte I, Nargi E, Lannutti A, Marchisio M, Pierdomenico L, Costanzo G, Iorio PD, Ballerini P, Giuliani P, Caciagli F, Ciccarelli R (2013) Adenosine A1 receptor stimulation enhances osteogenic differentiation of human dental pulp-derived mesenchymal stem cells via WNT signaling. Stem Cell Res 11(1):611–624. doi:10.1016/j.scr.2013.04.002

    Article  PubMed  Google Scholar 

  72. D’Alimonte I, Nargi E, Lannutti A, Marchisio M, Pierdomenico L, Costanzo G, Di Iorio P, Ballerini P, Giuliani P, Caciagli F (2013) Adenosine A1 receptor stimulation enhances osteogenic differentiation of human dental pulp-derived mesenchymal stem cells via WNT signaling. Stem Cell Res 11(1):611–624

    Article  PubMed  Google Scholar 

  73. Eijken M, Meijer IMJ, Westbroek I, Koedam M, Chiba H, Uitterlinden AG, Pols HAP, Van Leeuwen J (2008) Wnt signaling acts and is regulated in a human osteoblast differentiation dependent manner. J Cell Biochem 104(2):568–579

    Article  CAS  PubMed  Google Scholar 

  74. van der Horst G, van der Werf SM, Farih‐Sips H, van Bezooijen RL, Löwik CWGM, Karperien M (2005) Downregulation of Wnt signaling by increased expression of Dickkopf‐1 and‐2 is a prerequisite for late‐stage osteoblast differentiation of KS483 cells. J Bone Miner Res 20(10):1867–1877

    Article  PubMed  Google Scholar 

  75. De Mattei M, Caruso A, Traina GC, Pezzetti F, Baroni T, Sollazzo V (1999) Correlation between pulsed electromagnetic fields exposure time and cell proliferation increase in human osteosarcoma cell lines and human normal osteoblast cells in vitro. Bioelectromagnetics 20(3):177–182

    Article  PubMed  Google Scholar 

  76. Vincenzi F, Targa M, Corciulo C, Gessi S, Merighi S, Setti S, Cadossi R, Goldring MB, Borea PA, Varani K (2013) Pulsed electromagnetic fields increased the anti-inflammatory effect of A 2A and A 3 adenosine receptors in human T/C-28a2 Chondrocytes and hFOB 1.19 Osteoblasts. PLoS One 8(5):e65561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mediero A, Wilder T, Perez-Aso M, Cronstein BN (2015) Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2. FASEB J 29(4):1577–1590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. He W, Mazumder A, Wilder T, Cronstein BN (2013) Adenosine regulates bone metabolism via A1, A2A, and A2B receptors in bone marrow cells from normal humans and patients with multiple myeloma. FASEB J 27(9):3446–3454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Glassman SD, Howard J, Dimar J, Sweet A, Wilson G, Carreon L (2011) Complications with recombinant human bone morphogenic protein-2 in posterolateral spine fusion: a consecutive series of 1037 cases. Spine 36(22):1849–1854

    Article  PubMed  Google Scholar 

  80. 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(5):1353–1366

    Article  CAS  PubMed  Google Scholar 

  81. Rao V, Shih Y-RV, Kang H, Kabra H, Varghese S (2015) Adenosine signaling mediates osteogenic differentiation of human embryonic stem cells on mineralized matrices. Front Bioeng Biotechnol 3:185

    Article  PubMed  PubMed Central  Google Scholar 

  82. Trincavelli ML, Daniele S, Giacomelli C, Taliani S, Da Settimo F, Cosimelli B, Greco G, Novellino E, Martini C (2014) Osteoblast differentiation and survival: a role for A 2B adenosine receptor allosteric modulators. Biochim Biophys Acta 1843(12):2957–2966

    Article  CAS  PubMed  Google Scholar 

  83. Ham J, Evans BAJ (2012) An emerging role for adenosine and its receptors in bone homeostasis. Front Endocrinol 3:113

    Article  Google Scholar 

  84. Hsiao EC, Boudignon BM, Chang WC, Bencsik M, Peng J, Nguyen TD, Manalac C, Halloran BP, Conklin BR, Nissenson RA (2008) Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass. Proc Natl Acad Sci 105(4):1209–1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hajjawi MOR, Patel JJ, Corcelli M, Arnett TR, Orriss IR (2016) Lack of effect of adenosine on the function of rodent osteoblasts and osteoclasts in vitro. Purinergic Signalling 12(2):247–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Muir H (1995) The chondrocyte, architect of cartilage. Biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. Bioessays 17(12):1039–1048

    Article  CAS  PubMed  Google Scholar 

  87. Sandell LJ, Aigner T (2001) Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res 3(2):107–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tesch AM, MacDonald MH, Kollias-Baker C, Benton HP (2002) Effects of an adenosine kinase inhibitor and an adenosine deaminase inhibitor on accumulation of extracellular adenosine by equine articular chondrocytes. Am J Vet Res 63(11):1512–1519

    Article  CAS  PubMed  Google Scholar 

  89. Mistry D, Chambers MG, Mason RM (2006) The role of adenosine in chondrocyte death in murine osteoarthritis and in a murine chondrocyte cell line. Osteoarthr Cartil 14(5):486–495

    Article  CAS  PubMed  Google Scholar 

  90. Schaeffer HJ, Schwender CF (1974) Enzyme inhibitors. 26. Bridging hydrophobic and hydrophilic regions on adenosine deaminase with some 9-(2-hydroxy-3-alkyl) adenines. J Med Chem 17(1):6–8

    Article  CAS  PubMed  Google Scholar 

  91. 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(3):668–674

    Article  CAS  PubMed  Google Scholar 

  92. Sari RA, Taysi S, Yilmaz O, Bakan N (2002) Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis. Clin Exp Rheumatol 21(1):87–90

    Article  Google Scholar 

  93. Tesch AM, MacDonald MH, Kollias-Baker C, Benton HP (2004) Endogenously produced adenosine regulates articular cartilage matrix homeostasis: enzymatic depletion of adenosine stimulates matrix degradation. Osteoarthr Cartil 12(5):349–359

    Article  CAS  PubMed  Google Scholar 

  94. 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(2):258–267

    Article  CAS  PubMed  Google Scholar 

  95. Bitto A, Polito F, Irrera N, D’Ascola A, Avenoso A, Nastasi G, Campo GM, Micali A, Bagnato G, Minutoli L (2011) Polydeoxyribonucleotide reduces cytokine production and the severity of collagen‐induced arthritis by stimulation of adenosine A2A receptor. Arthritis Rheum 63(11):3364–3371

    Article  CAS  PubMed  Google Scholar 

  96. 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(12):2120–2133

    Article  CAS  PubMed  Google Scholar 

  97. 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(10):2119–2129

    Article  CAS  PubMed  Google Scholar 

  98. Stefanovic V, Vlahovic P, Savic V, Ardaillou N, Ardaillou R (1993) Adenosine stimulates 5′‐nucleotidase activity in rat mesangial cells via A2 receptors. FEBS Lett 331(1–2):96–100

    Article  CAS  PubMed  Google Scholar 

  99. Morabito L, Montesinos MC, Schreibman DM, Balter L, Thompson LF, Resta R, Carlin G, Huie MA, Cronstein BN (1998) Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5′-nucleotidase-mediated conversion of adenine nucleotides. J Clin Investig 101(2):295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Tenenbaum J, Muniz O, Ralph Schumacher H, Good AE, Howell DS (1981) Comparison of phosphohydrolase activities from articular cartilage in calcium pyrophosphate deposition disease and primary osteoarthritis. Arthritis Rheum 24(3):492–500

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Institutes of Health (AR056672, AR068593) and the NYU-HHC Clinical and Translational Science Institute (UL1TR000038).

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Authors and Affiliations

  1. Department of Medicine, School of Medicine, New York University , New York, NY, 10016, USA

    Lauren C. Strazzulla

  2. Divisions of Rheumatology and Translational Medicine, Department of Medicine, School of Medicine, New York University, 550 First Avenue, MSB251, New York, NY, 10016, USA

    Bruce N. Cronstein

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Correspondence to Bruce N. Cronstein.

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This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of Interest

Lauren Strazzulla, none. Bruce Cronstein, Consultations: AstraZeneca, Eli Lilly & Co., Bristol-Myers, Squibb. Grants: Celgene, AstraZeneca, Gilead. Equity: CanFite BioPharma. Intellectual Property: Multiple issued and pending patents assigned to NYU School of Medicine.

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Strazzulla, L.C., Cronstein, B.N. Regulation of bone and cartilage by adenosine signaling. Purinergic Signalling 12, 583–593 (2016). https://doi.org/10.1007/s11302-016-9527-2

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  • DOI: https://doi.org/10.1007/s11302-016-9527-2

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