Intra-articular injection of tumor necrosis factor-α in the rat: an acute and reversible in vivo model of cartilage proteoglycan degradation

Malfait, Anne‐Marie; Tortorella, Micky D.; Thompson, John F.; Hills, Robert L.; Meyer, Debra M.; Jaffee, Bruce; Chinn, Kathryn; Ghoreishi-Haack, Nayereh; Markosyan, Stella; Arner, Elizabeth C.

doi:10.1016/j.joca.2008.10.005

Cited by 26 publications

(22 citation statements)

References 41 publications

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“…These findings are furthermore consistent with previous in vitro and in vivo investigations showing that high concentrations of catabolic cytokines such as TNF-α lead to early (8 h to 2 days) aggrecanase activity [49, 50]. In agreement with Madsen et al [50], who used a similar bovine explant system, we did not detect MMP-generated FFGV fragments in the medium or in the cartilage during the 6 days of cartilage explant culture in the presence of TNF-α.…”

Section: Discussionsupporting

confidence: 92%

Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity

et al. 2017

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BackgroundA hallmark of osteoarthritis is increased proteolytic cleavage of aggrecan. Cross talk between cartilage and the synovium + joint capsule (SJC) can drive cartilage degradation by activating proteases in both tissues. We investigated aggrecan proteolysis patterns in cartilage explants using a physiologically relevant explant model of joint injury combining cartilage mechanical compression and coincubation with SJC.MethodsBovine cartilage explants were untreated; coincubated with SJC; or subjected to mechanical injury and coincubated with SJC, mechanical injury alone, or mechanical injury and incubated with tumor necrosis factor-α (TNF-α). To compare the patterns of aggrecan proteolysis between 6 h and 16 days, release of sulfated glycosaminoglycans and specific proteolytic aggrecan fragments into medium or remaining in cartilage explants was measured by dimethylmethylene blue and Western blot analysis.ResultsAggrecanase activity toward aggrecan was observed in all conditions, but it was directed toward the TEGE↓ARGS interglobular domain (IGD) site only when cartilage was coincubated with SJC or TNF-α. Matrix metalloproteinase (MMP) activity at the aggrecan IGD site (IPES↓FFGV) was not detected when cartilage was exposed to TNF-α (up to 6 days), but it was in all other conditions. Compared with when bovine cartilage was left untreated or subjected to mechanical injury alone, additional aggrecan fragment types were released into medium and proteolysis of aggrecan started at an earlier time when SJC was present.ConclusionsIndicative of different proteolytic pathways for aggrecan degradation, the SJC increases both aggrecanase and MMP activity toward aggrecan, whereas TNF-α inhibits MMP activity against the IGD of aggrecan.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1318-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity

et al. 2017

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“…Thus, the inhibitory effect of DEX on matrix degradation may involve modulating the proteolytic activities of aggrecanases. Recently, Malfait et al demonstrated that DEX blocked aggrecanase activity in an in vivo model of cartilage degradation: intra-articular injection of TNFα in rats resulted in aggrecanase-generated proteoglycan degradation, which could be inhibited by either an aggrecanase inhibitor or DEX, but not a non-steroidal anti-inflammatory drug [44]. …”

Section: Discussionmentioning

confidence: 99%

Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines

Evans

Grodzinsky

2011

Arthritis Res Ther

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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.

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“…These models typically present as a mild, acute lesion relative to the joint alterations produced by other inciting agents. A sixth alternative is to inject proinflammatory cytokines directly into a joint (usually the tibiotarsal joint (knee) due to its large volume) to induce an acute synovitis [62, 63]. Interestingly, IL-1 β and TNF- α produce distinct, time-dependent patterns of acute arthritis in the rat knee following direct injection [62].…”

Section: Objective 1: Available Rodent Models Of Immune-mediated Amentioning

confidence: 99%

Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy

Bolon

Stolina

King

et al. 2010

BioMed Research International

121

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Rodent models of immune-mediated arthritis (RMIA) are the conventional approach to evaluating mechanisms of inflammatory joint disease and the comparative efficacy of antiarthritic agents. Rat adjuvant-induced (AIA), collagen-induced (CIA), and streptococcal cell wall-induced (SCW) arthritides are preferred models of the joint pathology that occurs in human rheumatoid arthritis (RA). Lesions of AIA are most severe and consistent; structural and immunological changes of CIA best resemble RA. Lesion extent and severity in RMIA depends on experimental methodology (inciting agent, adjuvant, etc.) and individual physiologic parameters (age, genetics, hormonal status, etc.). The effectiveness of antiarthritic molecules varies with the agent, therapeutic regimen, and choice of RMIA. All RMIA are driven by overactivity of proinflammatory pathways, but the dominant molecules differ among the models. Hence, as with the human clinical experience, the efficacy of various antiarthritic molecules differs among RMIA, especially when the agent is a specific cytokine inhibitor.

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Intra-articular injection of tumor necrosis factor-α in the rat: an acute and reversible in vivo model of cartilage proteoglycan degradation

Cited by 26 publications

References 41 publications

Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity

Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity

Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines

Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy

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