Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Inflammation
Published in: Inflammation 4/2018

01-08-2018 | REVIEW

The Role of Adenosine Receptor Activation in Attenuating Cartilaginous Inflammation

Authors: Jonathan M. Bekisz, Christopher D. Lopez, Carmen Corciulo, Aranzazu Mediero, Paulo G. Coelho, Lukasz Witek, Roberto L. Flores, Bruce N. Cronstein

Published in: Inflammation | Issue 4/2018

Login to get access

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.
Literature
1.
Haskó, G., and B.N. Cronstein. 2004. Adenosine: An endogenous regulator of innate immunity. Trends in Immunology 25: 33–39.CrossRefPubMed
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.CrossRef
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.
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.CrossRefPubMed
5.
Wuelling, M., and A. Vortkamp. 2010. Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification. Pediatric Nephrology 25: 625–631.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
8.
Cekic, C., and J. Linden. 2016. Purinergic regulation of the immune system. Nature Reviews. Immunology 16: 177–192.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRef
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.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.
Shum, L., and G. Nuckolls. 2002. The life cycle of chondrocytes in the developing skeleton. Arthritis Research 4: 94–106.CrossRefPubMed
21.
Hwang, H., and H. Kim. 2015. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. International Journal of Molecular Sciences 16: 26035–26054.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
23.
Kraan, V.P.M. 2012. Osteoarthritis year 2012 in review: Biology. Osteoarthritis and Cartilage 20: 1447–1450.CrossRefPubMed
24.
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.CrossRefPubMed
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.
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
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.CrossRef
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.CrossRefPubMed
Metadata
Title
The Role of Adenosine Receptor Activation in Attenuating Cartilaginous Inflammation
Authors
Jonathan M. Bekisz
Christopher D. Lopez
Carmen Corciulo
Aranzazu Mediero
Paulo G. Coelho
Lukasz Witek
Roberto L. Flores
Bruce N. Cronstein
Publication date
01-08-2018
Publisher
Springer US
Published in
Inflammation / Issue 4/2018
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-018-0781-z

Other articles of this Issue 4/2018

Inflammation 4/2018 Go to the issue

ORIGINAL ARTICLE

Protective Effect of Apigenin on Acrylonitrile-Induced Inflammation and Apoptosis in Testicular Cells via the NF-κB Pathway in Rats

ORIGINAL ARTICLE

Artesunate Inhibits Renal Ischemia-Reperfusion-Mediated Remote Lung Inflammation Through Attenuating ROS-Induced Activation of NLRP3 Inflammasome

ORIGINAL ARTICLE

Geniposide Attenuates LPS-Induced Injury via Up-Regulation of miR-145 in H9c2 Cells

ORIGINAL ARTICLE

M1 Macrophages but Not M2 Macrophages Are Characterized by Upregulation of CRP Expression via Activation of NFκB: a Possible Role for Ox-LDL in Macrophage Polarization

REVIEW

Acute Inflammation and Metabolism

ORIGINAL ARTICLE

NLRP3 Inflammasome Involves in the Acute Exacerbation of Patients with Chronic Obstructive Pulmonary Disease

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits