P141 NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) IS PRODUCED BY IL-1ě-STIMULATED HUMAN OSTEOARTHRITIS CHONDROCYTES AND PROTECTS MMP-9 FROM DEGRADATION

Gupta, Kamesh; Shukla, Monu Kumar; Malemud, Charles J.; Cowland, Jack B.; Haqqi, Tariq M.

doi:10.1016/s1063-4584(07)60593-7

Cited by 3 publications

(5 citation statements)

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“…This result contrasted with previous results obtained for NGAL production by human osteoarthritis chondrocytes in response to rhIL-1β [9]. This difference may merely represent a differential response of human chondrocytes to IL-1β versus IL-6 or differences between human OA chondrocytes and the C28/I2 human chondrocyte line.…”

Section: Discussioncontrasting

confidence: 99%

“…The rationale for analyzing NGAL production by C28/I2 chondrocytes stemmed from our previously reported finding that chondrocytes obtained from human osteoarthritis knee cartilage synthesized NGAL in response to IL-1β [9]. In addition, we showed that NGAL in synovial fluids obtained from patients with end-stage osteoarthritis was found in a complex with MMP-9.…”

Section: Introductionmentioning

confidence: 99%

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Blockade of recombinant human IL-6 by tocilizumab suppresses matrix metalloproteinase-9 production in the C28/I2 immortalized human chondrocyte cell line

Meszaros¹,

Dahoud²,

Mesiano³

et al. 2015

Integr Mol Med

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Two immortalized human juvenile chondrocyte cell lines, T/C28a2 and C28/I2, were employed to determine the extent to which recombinant human (rh) IL-6 or rh-TNF-α increased the production of matrix metalloproteinase-9 (MMP-9). The effect of rhIL-6 on neutrophil gelatinase-associated lipocalin (NGAL) was also assessed. Although C28/I2 chondrocytes incubated with rhIL-6 (50 ng/ml) increased MMP-9 production which could not be mimicked by the T/C28a2 chondrocyte line, the effect of rhTNF-α on MMP-9 was more robust than with rhIL-6. The combinations of rhIL-6 and soluble IL-6 receptor-α (sIL-6Rα) or rhIL-6 and tocilizumab (TCZ), a fully-humanized recombinant monoclonal antibody that neutralizes the interaction between IL-6 and IL-6R significantly reduced MMP-9 production by C28/I2 chondrocytes. However, TCZ had no effect on rhTNF-α-induced MMP-9 production. By contrast, rhIL-6 did not increase the production of NGAL by C28/I2 chondrocytes although the number of NGAL-positive cells was significantly reduced by sIL-6R compared to its control group, but not by the combination of rhIL-6 plus TCZ compared to rhIL-6. In summary, these results showed that rhIL-6 stimulated the production of MMP-9, but not NGAL, in the C28/I2 chondrocyte line. TCZ or sIL-6Rα suppressed rhIL-6-induced MMP-9 production.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blockade of recombinant human IL-6 by tocilizumab suppresses matrix metalloproteinase-9 production in the C28/I2 immortalized human chondrocyte cell line

Meszaros¹,

Dahoud²,

Mesiano³

et al. 2015

Integr Mol Med

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“…We have previously shown that human chondrocytes enzymatically dissociated from OA knee cartilage synthesized neutrophil gelatinase-associated lipocalin (NGAL) in response to exogenous IL-1β [ 98 ]. Importantly, we have also previously shown that NGAL exists in a complex with MMP-9 (92 kDa gelatinase; gelatinase B) in synovial fluids sampled from OA patients undergoing joint replacement surgery [ 99 ].…”

Section: A Role For the Adams In Oa?mentioning

confidence: 99%

“…The experimental results cited in references [ 98 – 100 , 102 ] were supported by grants from Genentech/Roche Group (South San Francisco, CA), by the CWRU Visual Sciences Research Center Core Grant, P30-EY-11373 and, by grants R01 AR-48782 and AT-002258 from the National Institutes of Health.…”

mentioning

confidence: 99%

A Role for Soluble IL-6 Receptor in Osteoarthritis

Akeson

Malemud

2017

JFMK

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Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines present at elevated levels in the synovial fluid of individuals with confirmed clinical diagnosis of rheumatoid arthritis (RA) and osteoarthritis (OA). The mechanism of action of IL-6 was shown to involve its capacity to interact with a membrane-bound IL-6 receptor (mIL-6Rα), also known as the “classical” IL-6 pathway, or through its interaction with a soluble IL-6 receptor (sIL-6R) termed the “trans-signaling” pathway. Activation of downstream signaling is transduced via these IL-6 receptors and principally involves the Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) signaling pathway that is further regulated by glycoprotein-130 (gp130) interacting with the IL-6/mIL-6R complex. Phosphorylation of STAT proteins via JAK activation facilitates STAT proteins to act as transcription factors in inflammation. However, the biological function(s) of the sIL-6R in human chondrocytes requires further elucidation, although we previously showed that exogenous sIL-6R significantly suppressed the synthesis of neutrophil gelatinase-associated lipocalin (NGAL) in the immortalized line of human chondrocytes, C28/I2. NGAL was shown to regulate the activity of matrix metalloproteinase-9 (MMP-9), whose activity is crucial in OA for the destruction of articular cartilage. The “shedding” of sIL-6R from the plasma membrane is carried out by a family of enzymes known as A Distintegrin and Metalloproteinase (ADAM), which are also elevated in OA. In this paper, we have systematically reviewed the role played by IL-6 in OA. We have proposed that sIL-6R may be an important target for future drug development in OA by ameliorating cartilage extracellular protein degradation.

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“…NGAL recovered from the synovial fluid of patients with end-stage OA of the knee could be a product released from neutrophils, but could also be synthesized by articular chondrocytes because human chondrocytes derived from OA knee cartilage and treated in culture with IL-1β were shown to synthesize NGAL [Gupta et al . 2006].…”

Section: Limiting the Activity Of Mmps In Osteoarthritis By Promotingmentioning

confidence: 99%

Prospects for treating osteoarthritis: enzyme–protein interactions regulating matrix metalloproteinase activity

Meszaros

Malemud

2012

Therapeutic Advances in Chronic Disease

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Primary osteoarthritis (OA) is a musculoskeletal disorder of unknown etiology. OA is characterized by an imbalance between anabolism and catabolism in, and altered homeostasis of articular cartilage. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motif are upregulated in OA joints. Extracellular matrix (ECM) proteins are critical for resistance to compressive forces and for maintaining the tensile properties of the tissue. Tissue inhibitor of metalloproteinases (TIMPs) is the endogenous inhibitor of MMPs, but in OA, TIMPs do not effectively neutralize MMP activity. Upregulation of MMP gene expression occurs in OA in a milieu of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor α. Presently, the medical therapy of OA includes mainly nonsteroidal anti-inflammatory drugs and corticosteroids which dampen pain and inflammation but appear to have little effect on restoring joint function. Experimental interventions to restore the imbalance between anabolism and catabolism include small molecule inhibitors of MMP subtypes or inhibitors of the interaction between IL-1 and its receptor. Although these agents have some positive effects on reducing MMP subtype activity they have little efficacy at the clinical level. MMP-9 is one MMP subtype implicated in the degradation of articular cartilage ECM proteins. MMP-9 was found in OA synovial fluid as a complex with neutrophil gelatinase-associated lipocalin (NGAL) which protected MMP-9 from autodegradation. Suppressing NGAL synthesis or promoting NGAL degradation may result in reducing the activity of MMP-9. We also propose initiating a search for enzyme-protein interactions to dampen other MMP subtype activity which could suppress ECM protein breakdown.

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P141 NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) IS PRODUCED BY IL-1ě-STIMULATED HUMAN OSTEOARTHRITIS CHONDROCYTES AND PROTECTS MMP-9 FROM DEGRADATION

Cited by 3 publications

References 0 publications

Blockade of recombinant human IL-6 by tocilizumab suppresses matrix metalloproteinase-9 production in the C28/I2 immortalized human chondrocyte cell line

Blockade of recombinant human IL-6 by tocilizumab suppresses matrix metalloproteinase-9 production in the C28/I2 immortalized human chondrocyte cell line

A Role for Soluble IL-6 Receptor in Osteoarthritis

Prospects for treating osteoarthritis: enzyme–protein interactions regulating matrix metalloproteinase activity

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