The Role of Adenosine Receptor Activation in Attenuating Cartilaginous Inflammation

Abstract

Adenosine receptor activation has been explored as a modulator of the inflammatory process that propagates osteoarthritis. It has been reported that cartilage has enhanced regenerative potential when influenced by adenosine receptor activation. As adenosine’s role in maintaining chondrocyte homeostasis at the cellular and molecular levels is explored, successful in vivo applications of adenosine delivery for cartilage repair continue to be reported. This review summarizes the role adenosine receptor ligation plays in chondrocyte homeostasis and regeneration of articular cartilage damaged in osteoarthritis. It also reports on all the modalities reported for delivery of adenosine through in vivo applications.

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References

  1. 1.

    Haskó, G., and B.N. Cronstein. 2004. Adenosine: An endogenous regulator of innate immunity. Trends in Immunology 25: 33–39.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Haskó, G., P. Pacher, E.A. Deitch, and S.E. Vizi. 2007. Shaping of monocyte and macrophage function by adenosine receptors. Pharmacology & Therapeutics 113: 264–275.

    Article  CAS  Google Scholar 

  3. 3.

    Hall, B.K., and T. Miyake. 2004. Divide, accumulate, differentiate: cell condensation in skeletal development revisited. International Journal of Developmental Biology 39(6): 881–93.

  4. 4.

    Borea, P.A., S. Gessi, S. Merighi, and K. Varani. 2016. Adenosine as a multi-signalling guardian angel in human diseases: When, where and how does it exert its protective effects? Trends in Pharmacological Sciences 37: 419–434.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Wuelling, M., and A. Vortkamp. 2010. Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification. Pediatric Nephrology 25: 625–631.

    Article  PubMed  Google Scholar 

  6. 6.

    Ohta, A., and M. Sitkovsky. 2001. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414: 916–920.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. 7.

    Borea, P.A., S. Gessi, S. Merighi, F. Vincenzi, and K. Varani. 2017. Pathological overproduction: The bad side of adenosine. British Journal of Pharmacology 174: 1945–1960.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Cekic, C., and J. Linden. 2016. Purinergic regulation of the immune system. Nature Reviews. Immunology 16: 177–192.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Koszalka, P., M. Golunska, A. Urban, G. Stasilojc, M. Stanislawowski, M. Majewski, A.C. Skladanowski, and J. Bigda. 2016. Specific activation of A3, A2A and A1 adenosine receptors in CD73-knockout mice affects B16F10 melanoma growth, neovascularization, angiogenesis and macrophage infiltration. PLoS One 11: e0151420.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. 10.

    Zhou, Y., D.J. Schneider, E. Morschl, L. Song, M. Pedroza, H. Karmouty-Quintana, T. Le, C.X. Sun, and M.R. Blackburn. 2011. Distinct roles for the A2B adenosine receptor in acute and chronic stages of bleomycin-induced lung injury. Journal of Immunology 186: 1097–1106.

    Article  CAS  Google Scholar 

  11. 11.

    Rudich, N., O. Dekel, and R. Sagi-Eisenberg. 2015. Down-regulation of the A3 adenosine receptor in human mast cells upregulates mediators of angiogenesis and remodeling. Molecular Immunology 65: 25–33.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Kolachala, V., B. Ruble, M. Vijay-Kumar, L. Wang, S. Mwangi, H. Figler, R. Figler, S. Srinivasan, A. Gewirtz, J. Linden, D. Merlin, and S. Sitaraman. 2008. Blockade of adenosine A2B receptors ameliorates murine colitis. British Journal de Pharmacologie 155: 127–137.

    Article  CAS  Google Scholar 

  13. 13.

    Kolachala, V.L., M. Vijay-Kumar, G. Dalmasso, D. Yang, J. Linden, L. Wang, A. Gewirtz, K. Ravid, D. Merlin, and S.V. Sitaraman. 2008. A2B adenosine receptor gene deletion attenuates murine colitis. Gastroenterology 135: 861–870.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ingersoll, S.A., H. Laroui, V.L. Kolachala, L. Wang, P. Garg, T.L. Denning, A.T. Gewirtz, D. Merlin, and S.V. Sitaraman. 2012. A((2)B)AR expression in non-immune cells plays an important role in the development of murine colitis. Digestive and Liver Disease 44: 819–826.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Lee, J., I. Hwang, J.H. Lee, H.W. Lee, L.S. Jeong, and H. Ha. 2013. The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis. The American Journal of Pathology 183: 1488–1497.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Tang, J., X. Jiang, Y. Zhou, and Y. Dai. 2015. Effects of A2BR on the biological behavior of mouse renal fibroblasts during hypoxia. Molecular Medicine Reports 11: 4397–4402.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Yang, T., C. Zollbrecht, M.E. Winerdal, Z. Zhuge, X.M. Zhang, N. Terrando, A. Checa, J. Sallstrom, C.E. Wheelock, O. Winqvist, R.A. Harris, E. Larsson, A.E. Persson, B.B. Fredholm, and M. Carlstrom. 2016. Genetic abrogation of adenosine A3 receptor prevents uninephrectomy and high salt-induced hypertension. Journal of the American Heart Association 5: e003868.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Zhou, Y., J.N. Murthy, D. Zeng, L. Belardinelli, and M.R. Blackburn. 2010. Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. PLoS One 5: e9224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Long, F., X.M. Zhang, S. Karp, Y. Yang, and A.P. McMahon. 2001. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation Development. Development 128(24): 5099–108.

  20. 20.

    Shum, L., and G. Nuckolls. 2002. The life cycle of chondrocytes in the developing skeleton. Arthritis Research 4: 94–106.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Hwang, H., and H. Kim. 2015. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. International Journal of Molecular Sciences 16: 26035–26054.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. 22.

    Xia, B., D. Chen, J. Zhang, S. Hu, H. Jin, and P. Tong. 2014. Osteoarthritis pathogenesis: A review of molecular mechanisms. Calcified Tissue International 95: 495–505.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. 23.

    Kraan, V.P.M. 2012. Osteoarthritis year 2012 in review: Biology. Osteoarthritis and Cartilage 20: 1447–1450.

    Article  PubMed  Google Scholar 

  24. 24.

    Scanzello, C.R. 2017. Role of low-grade inflammation in osteoarthritis. Current Opinion in Rheumatology 29: 79–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Koolpe, M., D. Pearson, and H.P. Benton. 1999. Expression of both P1 and P2 purine receptor genes by human articular chondrocytes and profile of ligand-mediated prostaglandin E2 release. Arthritis and Rheumatism 42: 258–267.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Benton, H.P., and M.H. MacDonald. 2002. Effects of adenosine on bacterial lipopolysaccharide-and interleukin 1-induced nitric oxide release from equine articular chondrocytes, American Journal of Veterinary Research 63(2): 204–10.

  27. 27.

    Tesch, A.M., M.H. MacDonald, and C. Kollias-Baker. 2004. Endogenously produced adenosine regulates articular cartilage matrix homeostasis: Enzymatic depletion of adenosine stimulates matrix degradation. Osteoarthritis and Cartilage 12: 349–359.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Campo, G.M., A. Avenoso, and A. D’Ascola. 2012. Adenosine A2A receptor activation and hyaluronan fragment inhibition reduce inflammation in mouse articular chondrocytes stimulated with interleukin-1β. The FEBS Journal 279: 2120–2133.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Picher, M., R.D. Graff, and G.M. Lee. 2003. Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage. Arthritis & Rheumatology 48: 2722–2736.

    Article  CAS  Google Scholar 

  30. 30.

    Tesch, A.M., M.H. MacDonald, C. Kollias-Baker, and H.P. Benton. 2002. Effects of an adenosine kinase inhibitor and an adenosine deaminase inhibitor on accumulation of extracellular adenosine by equine articular chondrocytes. American Journal of Veterinary Research 63: 1512–1519.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Mistry, D., M.G. Chambers, and R.M. Mason. 2006. The role of adenosine in chondrocyte death in murine osteoarthritis and in a murine chondrocyte cell line. Osteoarthritis and Cartilage 14: 486–495.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Tesch, A.M., M.H. MacDonald, C. Kollias-Baker, and H.P. Benton. 2002. Chondrocytes respond to adenosine via A(2)receptors and activity is potentiated by an adenosine deaminase inhibitor and a phosphodiesterase inhibitor. Osteoarthritis and Cartilage 10: 34–43.

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Tesch, A.M., M.H. MacDonald, C. Kollias-Baker, and H.P. Benton. 2004. Endogenously produced adenosine regulates articular cartilage matrix homeostasis: Enzymatic depletion of adenosine stimulates matrix degradation. Osteoarthritis and Cartilage 12: 349–359.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Cederbaum, S.D., I. Kaitila, D.L. Rimoin, and E.R. Stiehm. 1976. The chondro-osseous dysplasia of adenosine deaminase deficiency with severe combined immunodeficiency. The Journal of Pediatrics 89: 737–742.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Benton, H.P., M.H. MacDonald, and A.M. Tesch. 2002. Effects of adenosine on bacterial lipopolysaccharide- and interleukin 1-induced nitric oxide release from equine articular chondrocytes. American Journal of Veterinary Research 63: 204–210.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Sari, R.A., S. Taysi, O. Yilmaz, and N. Bakan. 2003. Correlation of serum levels of adenosine deaminase activity and its isoenzymes with disease activity in rheumatoid arthritis. Clinical and Experimental Rheumatology 21: 87–90.

    PubMed  CAS  Google Scholar 

  37. 37.

    Nakamachi, Y., M. Koshiba, T. Nakazawa, S. Hatachi, R. Saura, M. Kurosaka, H. Kusaka, and S. Kumagai. 2003. Specific increase in enzymatic activity of adenosine deaminase 1 in rheumatoid synovial fibroblasts. Arthritis and Rheumatism 48: 668–674.

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Mazzon, E., E. Esposito, D. Impellizzeri, R. DI Paola, A. Melani, P. Bramanti, F. Pedata, and S. Cuzzocrea. 2011. CGS 21680, an agonist of the adenosine (A2A) receptor, reduces progression of murine type II collagen-induced arthritis. The Journal of Rheumatology 38: 2119–2129.

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Cronstein, B.N., M.A. Eberle, H.E. Gruber, and R.I. Levin. 1991. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proceedings of the National Academy of Sciences of the United States of America 88: 2441–2445.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. 40.

    Cronstein, B.N., D. Naime, and E. Ostad. 1993. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. The Journal of Clinical Investigation 92: 2675–2682.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. 41.

    Gadangi, P., M. Longaker, D. Naime, R.I. Levin, P.A. Recht, M.C. Montesinos, M.T. Buckley, G. Carlin, and B.N. Cronstein. 1996. The anti-inflammatory mechanism of sulfasalazine is related to adenosine release at inflamed sites. Journal of Immunology 156: 1937–1941.

    CAS  Google Scholar 

  42. 42.

    Mediero, A., M. Perez-Aso, and B.N. Cronstein. 2013. Activation of adenosine A(2A) receptor reduces osteoclast formation via PKA- and ERK1/2-mediated suppression of NFkappaB nuclear translocation. British Journal of Pharmacology 169: 1372–1388.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Mediero, A., T. Wilder, M. Perez-Aso, and B.N. Cronstein. 2015. Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2. The FASEB Journal 29: 1577–1590.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. 44.

    Morabito, L., M.C. Montesinos, D.M. Schreibman, L. Balter, L.F. Thompson, R. Resta, G. Carlin, M.A. Huie, and B.N. Cronstein. 1998. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5′-nucleotidase-mediated conversion of adenine nucleotides. The Journal of Clinical Investigation 101: 295–300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. 45.

    Gennero, L., T. Denysenko, G.F. Calisti, A. Vercelli, C.M. Vercelli, S. Amedeo, S. Mioletti, E. Parino, M. Montanaro, A. Melcarne, C. Juenemann, E. De Vivo, A. Longo, G. Cavallo, and R. De Siena. 2013. Protective effects of polydeoxyribonucleotides on cartilage degradation in experimental cultures. Cell Biochemistry and Function 31: 214–227.

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    Bitto, A., F. Polito, N. Irrera, A. D’Ascola, A. Avenoso, G. Nastasi, G.M. Campo, A. Micali, G. Bagnato, L. Minutoli, H. Marini, M. Rinaldi, F. Squadrito, and D. Altavilla. 2011. Polydeoxyribonucleotide reduces cytokine production and the severity of collagen-induced arthritis by stimulation of adenosine A((2)A) receptor. Arthritis and Rheumatism 63: 3364–3371.

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Vanelli, R., P. Costa, S.M. Rossi, and F. Benazzo. 2010. Efficacy of intra-articular polynucleotides in the treatment of knee osteoarthritis: A randomized, double-blind clinical trial. Knee Surgery, Sports Traumatology, Arthroscopy 18: 901–907.

    Article  PubMed  Google Scholar 

  48. 48.

    Giarratana, L.S., B.M. Marelli, C. Crapanzano, S.E. De Martinis, L. Gala, M. Ferraro, N. Marelli, and W. Albisetti. 2014. A randomized double-blind clinical trial on the treatment of knee osteoarthritis: The efficacy of polynucleotides compared to standard hyaluronian viscosupplementation. The Knee 21: 661–668.

    Article  PubMed  Google Scholar 

  49. 49.

    Allen, T.M., and P.R. Cullis. 2013. Liposomal drug delivery systems: From concept to clinical applications. Advanced Drug Delivery Reviews 65: 36–48.

    Article  PubMed  CAS  Google Scholar 

  50. 50.

    Corciulo, C., M. Lendhey, T. Wilder, H. Schoen, A.S. Cornelissen, G. Chang, O.D. Kennedy, and B.N. Cronstein. 2017. Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nature Communications 8: 15019.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Katebi, M., M. Soleimani, and B.N. Cronstein. 2009. Adenosine A2A receptors play an active role in mouse bone marrow-derived mesenchymal stem cell development. Journal of Leukocyte Biology 85: 438–444.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. 52.

    Song, L., N.E. Webb, Y. Song, and R.S. Tuan. 2006. Identification and functional analysis of candidate genes regulating mesenchymal stem cell self-renewal and multipotency. Stem Cells 24: 1707–1718.

    Article  PubMed  Google Scholar 

  53. 53.

    Delorme, B., J. Ringe, N. Gallay, Y. Le Vern, D. Kerboeuf, C. Jorgensen, P. Rosset, L. Sensebe, P. Layrolle, T. Haupl, and P. Charbord. 2008. Specific plasma membrane protein phenotype of culture-amplified and native human bone marrow mesenchymal stem cells. Blood 111: 2631–2635.

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    Chamberlain, G., J. Fox, B. Ashton, and J. Middleton. 2007. Concise review: Mesenchymal stem cells: Their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25: 2739–2749.

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Ode, A., J. Kopf, A. Kurtz, K. Schmidt-Bleek, P. Schrade, P. Kolar, F. Buttgereit, K. Lehmann, D.W. Hutmacher, G.N. Duda, and G. Kasper. 2011. CD73 and CD29 concurrently mediate the mechanically induced decrease of migratory capacity of mesenchymal stromal cells. European Cells & Materials 22: 26–42.

    Article  CAS  Google Scholar 

  56. 56.

    Kang, M.N., H.H. Yoon, Y.K. Seo, and J.K. Park. 2012. Effect of mechanical stimulation on the differentiation of cord stem cells. Connective Tissue Research 53: 149–159.

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Ode, A., J. Schoon, A. Kurtz, M. Gaetjen, J.E. Ode, S. Geissler, and G.N. Duda. 2013. CD73/5′-ecto-nucleotidase acts as a regulatory factor in osteo−/chondrogenic differentiation of mechanically stimulated mesenchymal stromal cells. European Cells & Materials 25: 37–47.

    Article  CAS  Google Scholar 

  58. 58.

    Napieralski, R., B. Kempkes, and W. Gutensohn. 2003. Evidence for coordinated induction and repression of ecto-5′-nucleotidase (CD73) and the A2a adenosine receptor in a human B cell line. Biological Chemistry 384: 483–487.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Jonathan M. Bekisz.

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Jonathan M. Bekisz and Christopher D. Lopez contributed equally to this work.

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Bekisz, J.M., Lopez, C.D., Corciulo, C. et al. The Role of Adenosine Receptor Activation in Attenuating Cartilaginous Inflammation. Inflammation 41, 1135–1141 (2018). https://doi.org/10.1007/s10753-018-0781-z

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KEY WORDS

  • tissue engineering
  • chondrocyte
  • cartilage
  • regeneration