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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Haskó, G., and B.N. Cronstein. 2004. Adenosine: An endogenous regulator of innate immunity. Trends in Immunology 25: 33–39.
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.
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.
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.
Wuelling, M., and A. Vortkamp. 2010. Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification. Pediatric Nephrology 25: 625–631.
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.
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.
Cekic, C., and J. Linden. 2016. Purinergic regulation of the immune system. Nature Reviews. Immunology 16: 177–192.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Shum, L., and G. Nuckolls. 2002. The life cycle of chondrocytes in the developing skeleton. Arthritis Research 4: 94–106.
Hwang, H., and H. Kim. 2015. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. International Journal of Molecular Sciences 16: 26035–26054.
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.
Kraan, V.P.M. 2012. Osteoarthritis year 2012 in review: Biology. Osteoarthritis and Cartilage 20: 1447–1450.
Scanzello, C.R. 2017. Role of low-grade inflammation in osteoarthritis. Current Opinion in Rheumatology 29: 79–85.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Allen, T.M., and P.R. Cullis. 2013. Liposomal drug delivery systems: From concept to clinical applications. Advanced Drug Delivery Reviews 65: 36–48.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Jonathan M. Bekisz and Christopher D. Lopez contributed equally to this work.
About this article
Cite this article
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
- tissue engineering