Mechanical Injury and Cytokines Cause Loss of Cartilage Integrity and Upregulate Proteins Associated with Catabolism, Immunity, Inflammation, and Repair

Stevens, Anna L.; Wishnok, John S.; White, Forest M.; Grodzinsky, Alan J.; Tannenbaum, Steven R.

doi:10.1074/mcp.m800181-mcp200

Cited by 96 publications

(107 citation statements)

References 86 publications

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“…Interestingly, a single-nucleotide polymorphism in FRZB, which negatively affects its function, is associated with OA (41). Increased levels of secreted FRZB were detected in cytokine-stimulated cartilage (35), which could correspond to the early secretion and loss from cartilage seen in our study, indicating the absence of new synthesis. Further, we observed a decrease in LECT2 levels in stimulated cartilage.…”

Section: Discussionmentioning

confidence: 69%

“…Further, cells responding to IL-1a in our model may be endothelial cells and resident immune cells, notably macrophages. The process of matrix degradation in cartilage explants after cytokine treatment was studied previously with MS, and the focus most often has been on the components released from cartilage (35)(36)(37). Because we were interested in investigating how alterations in the cartilage surface affect how it interacts with complement, we focused on determining the protein content in the residual cartilage explant upon IL-1a stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Quantitative Mass Spectrometry To Study Inflammatory Cartilage Degradation and Resulting Interactions with the Complement System

Fürst

Åhrman

Bratteby

et al. 2016

The Journal of Immunology

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Joint diseases are often characterized by inflammatory processes that result in pathological changes in joint tissues, including cartilage degradation and release of components into the synovial fluid. The complement system plays a central role in promoting the inflammation. Because several cartilage proteins are known to interact with complement, causing either activation or inhibition of the system, we aimed to investigate these interactions comprehensively. Bovine cartilage explants were cultured with IL-1α to induce cartilage degradation, followed by incubation with human serum. Label-free selected reaction monitoring mass spectrometry was used to specifically quantify complement proteins interacting with the cartilage explant. In parallel, the time-dependent degradation of cartilage was detected using mass spectrometry analysis (liquid chromatography–tandem mass spectrometry). Complement proteins resulting from activation of the classical, alternative, and terminal pathways were detected on IL-1α–stimulated cartilage at time points when clear alterations in extracellular matrix composition had occurred. Increased levels of the complement activation product C4d, as detected by ELISA in serum after incubation with IL-1α–stimulated cartilage, confirmed the selected reaction monitoring results indicating complement activation. Further, typical activated (cleaved) C3 fragments were detected by Western blotting in extracts of IL-1α–stimulated cartilage. No complement activation was triggered by cartilage cultured in the absence of IL-1α. Components released from IL-1α–stimulated cartilage during culture had an inhibitory effect on complement activation. These were released after a longer incubation period with IL-1α and may represent a feedback reaction to cartilage-triggered complement activation observed after a shorter incubation period.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Quantitative Mass Spectrometry To Study Inflammatory Cartilage Degradation and Resulting Interactions with the Complement System

Fürst

Åhrman

Bratteby

et al. 2016

The Journal of Immunology

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“…In addition, IL-1β exhibits inhibitory effects on collagen type II and aggrecan synthesis. Thus, IL-1β disrupts the balance of metabolism between catabolism and anabolism, which may result in articular cartilage destruction (29,30).…”

Section: Discussionmentioning

confidence: 99%

Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes

Wang

Li²,

Fan

et al. 2011

Int J Mol Med

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Abstract. Interleukin (IL)-1β plays an important role in the pathogenesis of osteoarthritis and catabolic processes in articular cartilage. Growing evidence suggests that ERK1/2 activation is involved in IL-1β-mediated matrix metalloproteinase (MMP) 3, MMP13, type II collagen and aggrecan expression in chondrocytes. To investigate the respective effects and the relationship of ERK1 and ERK2, knockdown of ERK1 and/or ERK2 was performed in human chondrocytes using specific small interfering RNAs (siRNAs), and the cells were treated with IL-1β (10 ng/ml) for 24 h. Uninfected chondrocytes treated with IL-1β (10 ng/ml) were used as a positive control. Other cells cultured without IL-1β or siRNA treatment were used as a negative control. The mRNA levels of MMP3, MMP13, type II collagen and aggrecan were evaluated by quantitative real-time PcR. The protein levels of MMP3 and MMP13 in the culture medium were examined by ELISA. The protein levels of type II collagen, aggrecan, ERK1/2 and phospho-ERK1/2 were evaluated by western blotting. The results indicate that IL-1β enhances MMP3 and MMP13 expression and inhibits type II collagen and aggrecan expression. Activation of the MAPK/ERK pathway was observed. Knockdown of ERK1 or ERK2 significantly reversed these effects to similar degree. combined knockdown of ERK1 and ERK2 displayed synergistic effects. ERK1 and phospho-ERK1 or ERK2 and phospho-ERK2 were inhibited by knockdown of ERK1 or ERK2, respectively. No compensatory effect by up-regulation of the opposite isoform was observed. The combined knockdown suppressed ERK1/2 and phospho-ERK1/2. The data suggest that although inhibition of both ERK1 and ERK2 is more effective, inhibition of either ERK isoform may be sufficient and could be used for novel therapies or as drug targets for pharmacological intervention in cartilage breakdown in osteoarthritis.

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“…Mechanical stress generates necrosis (4) and induces apoptosis (5) involving the release of reactive oxygen species (ROS) (6). Furthermore, an impact results in the early loss of glycosaminoglycans due to mechanical disruption of the cartilage extracellular matrix and a subsequent induction of degrading enzymes supporting cartilage degradation (7,8).…”

Section: Introductionmentioning

confidence: 99%

Single impact trauma in human early-stage osteoarthritic cartilage: Implication of prostaglandin D2 but no additive effect of IL-1β on cell survival

Joos

Hogrefe²,

Rieger³

et al. 2011

Int J Mol Med

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Abstract. Injury to articular cartilage is often associated with an inflammatory reaction and frequently results in the development of post-traumatic osteoarthritis (post-traumatic OA). Cell death, inflammation and loss of proteoglycans participate in these mechanisms with p38MAPK being one of the pivotal signaling kinases. Therefore, the interaction of trauma and of the pro-inflammatory cytokine IL-1β was investigated in an in vitro tissue model of human osteoarthritic cartilage. Trauma was induced by impacting cartilage explants with a drop-tower system and its effect was measured in terms of cell survival, gene expression and the release of mediators. In addition, the effect of concomitant IL-1β stimulation and p38MAPK inhibition by SB203580 was investigated. We found a significant decrease in chondrocyte viability after trauma, but no additional effect of IL-1β stimulation. SB203580 had a tendency to improve cell survival suggesting a role for p38 signaling in cell viability after impact in an inflammatory environment. We showed that various mediators are released in response to trauma with or without IL-1β stimulation, differing in composition and time response. Trauma resulted in an increased release of IL-6, whereas TNF-α and IL-1β release was unaffected. Prostaglandin (PG) and NO synthesis pathways were both affected by trauma and/ or IL-1β. We demonstrate for the first time an elevated release of prostaglandin D2 (PGD2) by human articular cartilage in response to a single mechanical impact. The up-regulation of mediators was time-dependent, with a more early increase of PGD2 compared to prostaglandin E2 (PGE2) and a late induction of NO by co-stimulation with IL-1β between 6 and 24 h.

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Mechanical Injury and Cytokines Cause Loss of Cartilage Integrity and Upregulate Proteins Associated with Catabolism, Immunity, Inflammation, and Repair

Cited by 96 publications

References 86 publications

Quantitative Mass Spectrometry To Study Inflammatory Cartilage Degradation and Resulting Interactions with the Complement System

Quantitative Mass Spectrometry To Study Inflammatory Cartilage Degradation and Resulting Interactions with the Complement System

Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes

Single impact trauma in human early-stage osteoarthritic cartilage: Implication of prostaglandin D2 but no additive effect of IL-1β on cell survival

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