Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines
Introduction: Traumatic joint injury damages cartilage and causes adjacent joint tissues to release inflammatory cytokines, increasing the risk of developing osteoarthritis. The main objective of this study was to determine whether the combined catabolic effects of mechanical injury, tumor necrosi...
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| Format: | Article |
| Language: | en_US |
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Biomed Central Ltd.
2012
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| Online Access: | http://hdl.handle.net/1721.1/75780 https://orcid.org/0000-0002-4942-3456 |
| _version_ | 1826192948792918016 |
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| author | Lu, Yihong C. S. Evans, Christopher H. Grodzinsky, Alan J. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Lu, Yihong C. S. Evans, Christopher H. Grodzinsky, Alan J. |
| author_sort | Lu, Yihong C. S. |
| collection | MIT |
| description | Introduction: Traumatic joint injury damages cartilage and causes adjacent joint tissues to release inflammatory
cytokines, increasing the risk of developing osteoarthritis. The main objective of this study was to determine
whether the combined catabolic effects of mechanical injury, tumor necrosis factor alpha (TNFa) and interleukin-6
(IL-6)/soluble IL-6 receptor (sIL-6R) on cartilage could be abolished by short-term treatment with glucocorticoids
such as dexamethasone.
Methods: In an initial dexamethasone-dose-response study, bovine cartilage explants were treated with TNFa and
increasing concentrations of dexamethasone. Bovine and human cartilage explants were then subjected to
individual and combined treatments with TNFa, IL-6/sIL-6R and injury in the presence or absence of
dexamethasone. Treatment effects were assessed by measuring glycosaminoglycans (GAG) release to the medium
and synthesis of proteoglycans. Additional experiments tested whether pre-exposure of cartilage to
dexamethasone could prevent GAG loss and inhibition of biosynthesis induced by cytokines, and whether posttreatment
with dexamethasone could diminish the effects of pre-established cytokine insult. Messenger ribonucleic
acid (mRNA) levels for genes involved in cartilage homeostasis (proteases, matrix molecules, cytokines, growth and
transcription factors) were measured in explants subjected to combined treatments with injury, TNFa and
dexamethasone. To investigate mechanisms associated with dexamethasone regulation of chondrocyte metabolic
response, glucocorticoid receptor (GR) antagonist (RU486) and proprotein convertase inhibitor (RVKR-CMK) were
used.
Results: Dexamethasone dose-dependently inhibited GAG loss and the reduction in biosynthesis caused by TNFa.
The combination of mechanical injury, TNFa and IL-6/sIL-6R caused the most severe GAG loss; dexamethasone
reduced this GAG loss to control levels in bovine and human cartilage. Additionally, dexamethasone pre-treatment
or post-treatment of bovine explants lowered GAG loss and increased proteoglycan synthesis in cartilage explants
exposed to TNFa. Dexamethasone did not down-regulate aggrecanase mRNA levels. Post-transcriptional regulation
by dexamethasone of other genes associated with responses to injury and cytokines was noted. GR antagonist
reversed the effect of dexamethasone on sulfate incorporation. RVKR-CMK significantly reduced GAG loss caused by
TNFa + IL-6 + injury.
Conclusions: Short-term glucocorticoid treatment effectively abolished the catabolic effects exerted by the
combination of pro-inflammatory cytokines and mechanical injury: dexamethasone prevented proteoglycan
degradation and restored biosynthesis. Dexamethasone appears to regulate the catabolic response of chondrocytes |
| first_indexed | 2024-09-23T09:31:39Z |
| format | Article |
| id | mit-1721.1/75780 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:31:39Z |
| publishDate | 2012 |
| publisher | Biomed Central Ltd. |
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| spelling | mit-1721.1/757802022-09-30T15:00:25Z Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines Lu, Yihong C. S. Evans, Christopher H. Grodzinsky, Alan J. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Lu, Yihong C. S. Grodzinsky, Alan J. Introduction: Traumatic joint injury damages cartilage and causes adjacent joint tissues to release inflammatory cytokines, increasing the risk of developing osteoarthritis. The main objective of this study was to determine whether the combined catabolic effects of mechanical injury, tumor necrosis factor alpha (TNFa) and interleukin-6 (IL-6)/soluble IL-6 receptor (sIL-6R) on cartilage could be abolished by short-term treatment with glucocorticoids such as dexamethasone. Methods: In an initial dexamethasone-dose-response study, bovine cartilage explants were treated with TNFa and increasing concentrations of dexamethasone. Bovine and human cartilage explants were then subjected to individual and combined treatments with TNFa, IL-6/sIL-6R and injury in the presence or absence of dexamethasone. Treatment effects were assessed by measuring glycosaminoglycans (GAG) release to the medium and synthesis of proteoglycans. Additional experiments tested whether pre-exposure of cartilage to dexamethasone could prevent GAG loss and inhibition of biosynthesis induced by cytokines, and whether posttreatment with dexamethasone could diminish the effects of pre-established cytokine insult. Messenger ribonucleic acid (mRNA) levels for genes involved in cartilage homeostasis (proteases, matrix molecules, cytokines, growth and transcription factors) were measured in explants subjected to combined treatments with injury, TNFa and dexamethasone. To investigate mechanisms associated with dexamethasone regulation of chondrocyte metabolic response, glucocorticoid receptor (GR) antagonist (RU486) and proprotein convertase inhibitor (RVKR-CMK) were used. Results: Dexamethasone dose-dependently inhibited GAG loss and the reduction in biosynthesis caused by TNFa. The combination of mechanical injury, TNFa and IL-6/sIL-6R caused the most severe GAG loss; dexamethasone reduced this GAG loss to control levels in bovine and human cartilage. Additionally, dexamethasone pre-treatment or post-treatment of bovine explants lowered GAG loss and increased proteoglycan synthesis in cartilage explants exposed to TNFa. Dexamethasone did not down-regulate aggrecanase mRNA levels. Post-transcriptional regulation by dexamethasone of other genes associated with responses to injury and cytokines was noted. GR antagonist reversed the effect of dexamethasone on sulfate incorporation. RVKR-CMK significantly reduced GAG loss caused by TNFa + IL-6 + injury. Conclusions: Short-term glucocorticoid treatment effectively abolished the catabolic effects exerted by the combination of pro-inflammatory cytokines and mechanical injury: dexamethasone prevented proteoglycan degradation and restored biosynthesis. Dexamethasone appears to regulate the catabolic response of chondrocytes National Institutes of Health (U.S.) (Grant AR045779) National Institutes of Health (U.S.) (Grant AR033236) 2012-12-18T19:04:25Z 2012-12-18T19:04:25Z 2011-09 2011-05 Article http://purl.org/eprint/type/JournalArticle 1478-6362 1478-6354 http://hdl.handle.net/1721.1/75780 Lu, Yihong CS, Christopher H Evans, and Alan J Grodzinsky. “Effects of Short-term Glucocorticoid Treatment on Changes in Cartilage Matrix Degradation and Chondrocyte Gene Expression Induced by Mechanical Injury and Inflammatory Cytokines.” Arthritis Research & Therapy 13.5 (2011): R142. https://orcid.org/0000-0002-4942-3456 en_US http://dx.doi.org/10.1186/ar3456 Arthritis Research and Therapy Creative Commons Attribution http://creativecommons.org/licenses/by/2.0 application/pdf Biomed Central Ltd. PMC |
| spellingShingle | Lu, Yihong C. S. Evans, Christopher H. Grodzinsky, Alan J. Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines |
| title | Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines |
| title_full | Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines |
| title_fullStr | Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines |
| title_full_unstemmed | Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines |
| title_short | Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines |
| title_sort | effects of short term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines |
| url | http://hdl.handle.net/1721.1/75780 https://orcid.org/0000-0002-4942-3456 |
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