Inhibition of adenosine kinase attenuates interleukin-1- and lipopolysaccharide-induced alterations in articular cartilage metabolism.
Abstract: To investigate the effect of adenosine kinase inhibition on interleukin (IL)-1beta- and lipopolysaccharide (LPS)-induced cartilage damage. Methods: Articular cartilage was obtained from the metacarpophalangeal joints of 10 young adult horses. Following a stabilization period, weighed cartilage explants were exposed to IL-1beta (10 ng/ml) or LPS (50 microg/ml) to induce cartilage degradation. To test the potential protective effects of adenosine, these explants were simultaneously exposed to adenosine (100 microM), the adenosine kinase inhibitor 5'iodotubercidin (ITU, 1 microM) or to both adenosine and ITU. After 72 h in culture, conditioned medium was collected for evaluation of glycosaminoglycan (GAG), nitric oxide (NO), prostaglandin E2 (PGE2) and matrix metalloproteinase (MMP)-3 release. Results: IL-1beta and LPS stimulated significant release of GAG, NO, PGE2 and MMP-3. Incubation with ITU significantly inhibited both IL-1beta- and LPS-induced GAG release, but did not alter MMP-3 production. Exposure to ITU also reduced IL-1beta-induced PGE2 release and LPS-induced NO production. Direct adenosine supplementation did not attenuate the effects of IL-1beta or LPS, and the addition of adenosine or ITU in the absence of IL-1beta or LPS did not have any detectable effect on cartilage metabolism in this model. Conclusions: The adenosine kinase inhibitor ITU attenuated experimentally induced cartilage damage in an in vitro cartilage explant model. Release of adenosine from chondrocytes may play a role in the cellular response to tissue damage in arthritic conditions and modulation of these pathways in the joint may have potential for treatment of arthropathies.
Publication Date: 2005-02-25 PubMed ID: 15727892DOI: 10.1016/j.joca.2004.12.004Google Scholar: Lookup
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Summary
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The research article concludes that inhibiting adenosine kinase (a type of enzyme) can potentially lessen the damage caused to cartilage by harmful substances interleukin-1beta and lipopolysaccharide.
Research Design and Experiment
- The researchers aimed to understand the impact of adenosine kinase inhibition on cartilage damage caused by interleukin (IL)-1beta and lipopolysaccharide (LPS).
- Articular cartilage (the type of cartilage found in joints) from the joints of 10 young horses was used in this experiment.
- The cartilage samples were left to stabilize before weights were taken and they were then subjected to IL-1beta or LPS to induce degradation.
- The protective effects of adenosine and the adenosine kinase inhibitor 5’iodotubercidin (ITU) were also tested. The samples were exposed to these alongside the IL-1beta and LPS.
- After 72 hours, the researchers collected medium from the experiment to measure levels of glycosaminoglycan (GAG), nitric oxide (NO), prostaglandin E2 (PGE2), and matrix metalloproteinase (MMP)-3, which are all indicators of cartilage health and metabolism.
Results and Findings
- IL-1beta and LPS exhibited a substantial release of GAG, NO, PGE2, and MMP-3, indicating cartilage damage.
- When the samples were treated with ITU, both IL-1beta- and LPS-induced GAG release considerably decreased, hinting at the protective effect of the adenosine kinase inhibitor. However, MMP-3 production was not altered.
- Exposure to ITU also reduced the release of PGE2 induced by IL-1beta and NO production induced by LPS.
- Adenosine supplementation did not have any noticeable impact on mitigating the damaging effects of IL-1beta or LPS. Similarly, using adenosine or ITU without the presence of IL-1beta or LPS did not affect cartilage metabolism in this model.
Conclusion
- The use of the adenosine kinase inhibitor ITU showed a significant reduction in experimentally induced cartilage damage in the in vitro model.
- Results suggest that the release of adenosine from chondrocytes (cartilage cells) possibly plays a role in how the cells respond to tissue damage in arthritis and similar conditions.
- Consequently, this pathway could be a target in arthritis treatment – possibly via use of adenosine kinase inhibitors to aid in the protection of cartilage.
Cite This Article
APA
Petrov R, MacDonald MH, Tesch AM, Benton HP.
(2005).
Inhibition of adenosine kinase attenuates interleukin-1- and lipopolysaccharide-induced alterations in articular cartilage metabolism.
Osteoarthritis Cartilage, 13(3), 250-257.
https://doi.org/10.1016/j.joca.2004.12.004 Publication
Researcher Affiliations
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA.
MeSH Terms
- Adenosine / pharmacology
- Adenosine Kinase / antagonists & inhibitors
- Animals
- Cartilage, Articular / drug effects
- Cartilage, Articular / metabolism
- Culture Media, Conditioned
- Dinoprostone / metabolism
- Enzyme Inhibitors / pharmacology
- Glycosaminoglycans / metabolism
- Horses
- Interleukin-1 / antagonists & inhibitors
- Interleukin-1 / toxicity
- Lipopolysaccharides / antagonists & inhibitors
- Lipopolysaccharides / toxicity
- Matrix Metalloproteinase 3 / metabolism
- Nitric Oxide / metabolism
- Tissue Culture Techniques / methods
- Tubercidin / analogs & derivatives
- Tubercidin / pharmacology
Citations
This article has been cited 9 times.- Pearson W, Garland AEN, Nixon A, Cant JP, Hurtig MB. Culturing Articular Cartilage Explants in the Presence of Autologous Adipose Tissue Modifies Their Inflammatory Response to Lipopolysaccharide. Mediators Inflamm 2020;2020:8811001.
- Corciulo C, Castro CM, Coughlin T, Jacob S, Li Z, Fenyö D, Rifkin DB, Kennedy OD, Cronstein BN. Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis. Sci Rep 2020 Aug 10;10(1):13477.
- Burnstock G, Arnett TR, Orriss IR. Purinergic signalling in the musculoskeletal system. Purinergic Signal 2013 Dec;9(4):541-72.
- Vincenzi F, Targa M, Corciulo C, Gessi S, Merighi S, Setti S, Cadossi R, Goldring MB, Borea PA, Varani K. Pulsed electromagnetic fields increased the anti-inflammatory effect of A₂A and A₃ adenosine receptors in human T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. PLoS One 2013;8(5):e65561.
- Boison D. Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 2013 Jul;65(3):906-43.
- Mediero A, Cronstein BN. Adenosine and bone metabolism. Trends Endocrinol Metab 2013 Jun;24(6):290-300.
- Cohen SB, Proudman S, Kivitz AJ, Burch FX, Donohue JP, Burstein D, Sun YN, Banfield C, Vincent MS, Ni L, Zack DJ. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Ther 2011 Jul 29;13(4):R125.
- Klawitter M, Quero L, Bertolo A, Mehr M, Stoyanov J, Nerlich AG, Klasen J, Aebli N, Boos N, Wuertz K. Human MMP28 expression is unresponsive to inflammatory stimuli and does not correlate to the grade of intervertebral disc degeneration. J Negat Results Biomed 2011 Jul 29;10:9.
- de Grauw JC, van de Lest CH, van Weeren PR. Inflammatory mediators and cartilage biomarkers in synovial fluid after a single inflammatory insult: a longitudinal experimental study. Arthritis Res Ther 2009;11(2):R35.
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