Abstract
IntroductionTraumatic 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 (TNFα) 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.MethodsIn an initial dexamethasone-dose-response study, bovine cartilage explants were treated with TNFα and increasing concentrations of dexamethasone. Bovine and human cartilage explants were then subjected to individual and combined treatments with TNFα, 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 post-treatment 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, TNFα 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.ResultsDexamethasone dose-dependently inhibited GAG loss and the reduction in biosynthesis caused by TNFα. The combination of mechanical injury, TNFα 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 TNFα. 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 TNFα + IL-6 + injury.ConclusionsShort-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 post-transcriptionally, since the abundance of transcripts encoding aggrecanases was still elevated in the presence of dexamethasone.
Highlights
Traumatic joint injury damages cartilage and causes adjacent joint tissues to release inflammatory cytokines, increasing the risk of developing osteoarthritis
DEX dose-dependently inhibited GAG loss and reversed the reduction in chondrocyte biosynthesis induced by tumor necrosis factor alpha (TNFa)-treatment of bovine cartilage Experiments were performed to test the effect of DEX (0.1 nM to 100 μM) on both TNFa-treated and untreated control cartilage explants (Figure 1)
Post-treatment with DEX reduced GAG loss and increased sulfate incorporation in TNFa-treated cartilage We examined whether DEX would exert anti-catabolic effects in cartilage samples where matrix degradation had already been induced by cytokine stimulation
Summary
Traumatic joint injury damages cartilage and causes adjacent joint tissues to release inflammatory cytokines, increasing the risk of developing osteoarthritis. Treatments following joint trauma initially focus on reducing pain and swelling, and often by subsequent reconstructive surgery to stabilize joint biomechanics, for example, for injuries involving anterior cruciate ligament (ACL) rupture. Joint injury results in an immediate surge in synovial fluid concentrations of pro-inflammatory cytokines, including tumor necrosis factor-a (TNFa), interleukin-1b (IL-1b), IL-6 and IL-8 [6,7,8]. The levels of these cytokines remain elevated for weeks and eventually decrease to levels detected in chronic OA joints [8]. Cartilage in the injured joint is often subjected to an initial biomechanical insult [9] and further compromised by the presence of high levels of inflammatory cytokines [10]
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