Nitric-Oxide Mediates Suppression of Cartilage Proteoglycan Synthesis by Interleukin-1

Taşkıran, Dilek; Stefanović-Račić, Maja; Georgescu, Helga I.; Evans, Caroline

doi:10.1006/bbrc.1994.1426

Cited by 342 publications

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“…The distribution and frequency of apoptosis among chondrocytes correlate with OA grade and proteoglycan depletion, suggesting a link between cell death and matrix degradation (36). High levels of nitrite/nitrate have been found in the synovial fluid and serum of OA patients, and it has been shown that NO causes loss of a differentiated phenotype and apoptosis of articular chondrocytes (36)(37)(38)(39). Specific inhibition of PKC inhibited basal as well as thyroid hormone-mediated stimulation of NOS in lymphocytes (40), suggesting a role of PKC in NOS activation.…”

Section: Discussionmentioning

confidence: 99%

Involvement of protein kinase Cζ in interleukin‐1β induction of ADAMTS‐4 and type 2 nitric oxide synthase via NF‐κB signaling in primary human osteoarthritic chondrocytes

Chockalingam¹,

Varadarajan²,

Sheldon³

et al. 2007

Arthritis & Rheumatism

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Objective. Protein kinase C (PKC ), an atypical PKC, has been found to be transcriptionally upregulated in human osteoarthritic (OA) articular cartilage. This study was undertaken to examine the role of PKC in interleukin-1␤ (IL-1␤)-induced NF-B signaling in human OA chondrocytes, and ultimately to better understand its function in the regulation of downstream mediators of cartilage matrix degradation.Methods. Pharmacologic inhibitors or genetic knockdown techniques were used to investigate the role of PKC . Western blot analysis was used to evaluate phosphorylation of PKC and NF-B. Quantitative polymerase chain reaction (PCR) and activity assays were used to evaluate ADAMTS-4 expression and aggrecanase activity, respectively. Quantitative PCR, biochemical identification, and Western blot analysis were used to evaluate type 2 nitric oxide synthase (NOS2) and NO production.Results. Phosphorylation of PKC and NF-B was induced by IL-1␤ treatment in a time-dependent manner, and was specifically inhibited by inhibitors of atypical PKCs. Inhibition of PKC suppressed IL-1␤-induced up-regulation of ADAMTS-4 messenger RNA (mRNA) and aggrecanase activity. Inhibitors of atypical PKCs also inhibited IL-1␤-induced NO production and NOS2 mRNA expression, demonstrating a novel link between PKC and NO production. Furthermore, small interfering RNA-or short hairpin RNA-mediated knockdown of PKC mRNA resulted in significant repression of both ADAMTS-4 and NOS2 mRNA expression. Conclusion. Our results show that PKC is involved in the regulation of IL-1␤-induced NF-B signaling in human OA chondrocytes, which in turn regulates downstream expression of ADAMTS-4 and NOS2.Therefore, inhibition of PKC could potentially regulate the production of matrix-degrading enzymes as well as NO production and have a profound effect on disease progression in OA.Osteoarthritis (OA) is a degenerative joint disorder characterized by destruction and loss of articular cartilage as a result of an imbalance between catabolic and anabolic cartilage matrix metabolism. It is the most common form of arthritis. Chondrocytes are the single cell type present in cartilage, and they play an important role in the pathogenesis of OA. They are the primary source of type II collagen and aggrecan, the most important components of the cartilage matrix. Cartilage loss in OA is characterized by matrix degradation and chondrocyte death.In OA, catabolic factors, including interleukin-1 (IL-1) and tumor necrosis factor (TNF), have been implicated in stimulating chondrocytes to produce matrix-degrading enzymes including aggrecanases (ADAMTS-4 and ADAMTS-5) and other metalloproteinases, resulting in degradation of aggrecan and collagen, respectively (1,2). Catabolic cytokines have also been demonstrated to induce synthesis of type 2 nitric oxide synthase (NOS2), resulting in the formation of nitric oxide (NO), an inducer of chondrocyte apoptosis (3). Studies of inducible NOS-null mice and investiga-

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Section: Discussionmentioning

confidence: 99%

Involvement of protein kinase Cζ in interleukin‐1β induction of ADAMTS‐4 and type 2 nitric oxide synthase via NF‐κB signaling in primary human osteoarthritic chondrocytes

Chockalingam¹,

Varadarajan²,

Sheldon³

et al. 2007

Arthritis & Rheumatism

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“…LPS is synergistic with muramyl dipeptide, a synthetic peptidoglycan monomer analogue, in the inhibition of proteoglycan synthesis in chondrocytes (Ikebe et al, 1993), an effect which may be mediated by NO? (Taskiran et al, 1994). Furthermore, a mixture of anhydrous muramyl peptide monomers, mostly TCT and the corresponding disaccharide±tripeptide derived from Neisseria gonorrhoeae, causes arthritic effects in cartilage (Fleming et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Signalling and cellular specificity of airway nitric oxide production in pertussis

Flak

Goldman

1999

Cell Microbiol

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SummaryBordetella pertussis, the aetiological agent of whooping cough (pertussis), causes selective destruction of ciliated cells of the human airway mucosa. In a hamster tracheal organ culture model, B. pertussis causes identical cytopathology as does tracheal cytotoxin (TCT), a glycopeptide released by the bacterium. The damage caused by B. pertussis or TCT has been shown to be mediated via nitric oxide (NO?). Using immuno¯uorescence detection of the cytokine-inducible NO synthase (iNOS; NOS type II), we determined that B. pertussis induced epithelial NO? production exclusively within non-ciliated cells. This epithelial iNOS activation could be reproduced by the combination of TCT and endotoxin. However, neither TCT alone nor endotoxin alone was capable of inducing epithelial iNOS. This result mirrors the synergistic activity of TCT and endotoxin exhibited in monolayer cultures of tracheal epithelial cells. Therefore, TCT and endotoxin are both important virulence factors of B. pertussis, combining synergistically to cause the speci®c epithelial pathology of pertussis.

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“…This activity has been attributed to the activation of the focal adhesion-associated tyrosine kinase pathway (14,15). Chondrocytes themselves express interleukin-1, which acts in a catabolic role by inducing cartilage damage through up-regulation of metalloproteases, reduction of proteoglycan synthesis, and stimulation of nitric oxide production (6,16).…”

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confidence: 99%

Characterization of metalloprotease cleavage products of human articular cartilage

Zhen¹,

Brittain²,

Laska³

et al. 2008

Arthritis & Rheumatism

137

125

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Objective. To identify, characterize, and compare proteolysis peptide products generated by metalloprotease digests of human articular cartilage.Methods. Human articular cartilage was digested by the addition of exogenous metalloproteases, including matrix metalloproteinases 2, 3, 8, 9, 12, and 13 and aggrecanases ADAMTS-4 and ADAMTS-5. Proteolyzed peptide products were identified by proteomics methods using mass spectrometry.Results. Complete sequences of the peptides proteolyzed from human articular cartilage, including Nand C-termini and hydroxylated posttranslational modifications, were determined. A wide variety of peptides, originating from types I, II, and III collagen, biglycan, prolargin, fibromodulin, fibronectin, decorin, cartilage oligomeric matrix protein, cartilage intermediate-layer protein, megakaryocyte-stimulating factor, mimecan, aggrecan, and lumican, was analyzed following metalloprotease digestion. Release of peptides varied as a function of time, enzyme specificity, and abundance. Specific type II collagen peptide biomarkers, including those containing the three-quarter-length fragment cleavage site and those containing the domains for helical peptide of type II collagen and C-telopeptide of type II collagen, were observed after release by selected proteases.Conclusion. The use of intact cartilage instead of purified protein substrates in the assay allowed for the identification of novel potential substrates and cleavage sites for individual enzymes under more physiologically relevant conditions. Characterization of these cartilage matrix peptides may help in the development of pharmacodynamic biomarkers of cartilage degradation, and also may contribute to an understanding of the bioactive peptides important in chondrocyte signaling.Osteoarthritis (OA) and rheumatoid arthritis (RA) are typified by biologic changes in the articular cartilage that lead to cartilage degradation and joint space narrowing (1,2). Articular cartilage is composed of 2 primary matrix proteins, type II collagen and aggrecan, as well as a number of other matrix proteins that provide structural functions such as rigidity, flexibility, and compression damping. In addition, the cartilage matrix influences chondrocyte function through integrin receptor signaling, initiated via ligation of either intact matrix molecules or peptide fragments resulting from proteolytic activity (3).In arthritis, an imbalance of chondrocyte matrix synthesis and degradation leads to a net loss of matrix, and eventually to joint impairment. In OA, the excessive degradation is primarily due to the action of proteases released by chondrocytes, synovial cells, and macrophages (4). Numerous serine proteases and metalloproteases are overexpressed by these cells during the disease process, but specific metalloproteases, including the collagenase matrix metalloproteinase 13 (MMP-13) and the aggrecanase ADAMTS-5, are thought to be especially important for initiating and promoting cartilage matrix degradation in OA (5,6). MMP-13 cleaves type II collage...

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Nitric-Oxide Mediates Suppression of Cartilage Proteoglycan Synthesis by Interleukin-1

Cited by 342 publications

References 0 publications

Involvement of protein kinase Cζ in interleukin‐1β induction of ADAMTS‐4 and type 2 nitric oxide synthase via NF‐κB signaling in primary human osteoarthritic chondrocytes

Involvement of protein kinase Cζ in interleukin‐1β induction of ADAMTS‐4 and type 2 nitric oxide synthase via NF‐κB signaling in primary human osteoarthritic chondrocytes

Signalling and cellular specificity of airway nitric oxide production in pertussis

Characterization of metalloprotease cleavage products of human articular cartilage

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