Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes.

Goldring, Mary B.; Birkhead, James R.; Sandell, Linda J.; Kimura, Tomio; Krane, Stephen M.

doi:10.1172/jci113823

Cited by 369 publications

(238 citation statements)

References 43 publications

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“…The meniscus is composed primarily of type I collagen; therefore incorporation of [ 3 H]proline is likely to reflect predominantly collagen I synthesis. This finding is in general agreement with previous reports that IL-1 can increase collagen I and III gene expression and decrease collagen II expression (22). Cao and associates (5) also showed that IL-1 reduced collagen synthesis, whereas total protein synthesis was unaffected as measured by [ 3 H]proline incorporation in meniscal culture.…”

Section: Discussionsupporting

confidence: 93%

Regulation of matrix turnover in meniscal explants: role of mechanical stress, interleukin-1, and nitric oxide

Shin¹,

Fermor²,

Weinberg³

et al. 2003

Journal of Applied Physiology

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. Regulation of matrix turnover in meniscal explants: role of mechanical stress, interleukin-1, and nitric oxide. J Appl Physiol 95: 308-313, 2003. First published March 28, 2003 10.1152/ japplphysiol.00131.2003The meniscus is an intra-articular fibrocartilaginous structure that serves essential biomechanical roles in the knee. With injury or arthritis, the meniscus may be exposed to significant changes in its biochemical and biomechanical environments that likely contribute to the progression of joint disease. The goal of this study was to examine the influence of mechanical stress on matrix turnover in the meniscus in the presence of interleukin-1 (IL-1) and to determine the role of nitric oxide (NO) in these processes. Explants of porcine menisci were subjected to dynamic compressive stresses at 0.1 MPa for 24 h at 0.5 Hz with 1 ng/ml IL-1, and the synthesis of total protein, proteoglycan, and NO was measured. The effects of a nitric oxide synthase 2 (NOS2) inhibitor were determined. Dynamic compression significantly increased protein and proteoglycan synthesis by 68 and 58%, respectively, compared with uncompressed explants. This stimulatory effect of mechanical stress was prevented by the presence of IL-1 but was restored by specifically inhibiting NOS2. Release of proteoglycans into the medium was increased by IL-1 or mechanical compression and further enhanced by IL-1 and compression together. Stimulation of proteoglycan release in response to compression was dependent on NOS2 regardless of the presence of IL-1. These finding suggest that IL-1 may modulate the effects of mechanical stress on extracellular matrix turnover through a pathway that is dependent on NO.

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Section: Discussionsupporting

confidence: 93%

Regulation of matrix turnover in meniscal explants: role of mechanical stress, interleukin-1, and nitric oxide

Shin¹,

Fermor²,

Weinberg³

et al. 2003

Journal of Applied Physiology

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“…This cytokine is present in osteoarthritic cartilage at both early and late stages of OA, as shown by in vivo studies (13,14). It has been shown that IL-1␤ down-regulates the biosynthesis of cartilage phenotypic markers, including type II collagen, whose mRNAs level is reduced by the cytokine (20,25). However, the mechanisms underlying IL-1␤ regulation of matrix genes in normal and osteoarthritic cartilage, particularly the set of transcription factors involved, are not completely understood.…”

Section: Sp3/sp1 Ratio Mediates Il-1␤ Inhibition Of Col2a1 Genementioning

confidence: 91%

Sp1 and Sp3 Transcription Factors Mediate Interleukin-1β Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes

Chadjichristos¹,

Ghayor²,

Kypriotou³

et al. 2003

Journal of Biological Chemistry

118

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Interleukin-1␤ (IL-1␤) is a pleiotropic cytokine that was shown to inhibit the biosynthesis of articular cartilage components. Here we demonstrate that IL-1␤ inhibits the production of newly synthesized collagens in proliferating rabbit articular chondrocytes and that this effect is accompanied by a decrease in the steady-state levels of type II collagen mRNA. IL-1␤ down-regulates COL2A1 gene transcription through a ؊41/؊33 bp sequence that binds a multimeric complex including Sp1 and Sp3 transcription factors. Specificity of IL-1␤ effects on COL2A1 promoter activity was demonstrated in experiments in which transfection of a wild type ؊50/؉1 sequence of COL2A1 promoter as a decoy oligonucleotide abolished the IL-1␤ inhibition of a ؊63/؉47 COL2A1-mediated transcription. By contrast, transfection of the related oligonucleotide harboring a targeted mutation in the ؊41/؊33 sequence did not modify the negative effect the cytokine. Because we demonstrated previously that Sp1 was a strong activator of COL2A1 gene expression via the ؊63/؉1 promoter region, whereas Sp3 overexpression blocked Sp1-induced promoter activity and inhibited COL2A1 gene transcription, we conclude that IL-1␤ down-regulation of that gene, as we found previously for transforming growth factor-␤1, is mediated by an increase in the Sp3/Sp1 ratio. Moreover, IL-1␤ increased steady-state levels of Sp1 and Sp3 mRNAs, whereas it enhanced Sp3 protein expression and inhibited Sp1 protein biosynthesis. Nevertheless, IL-1␤ decreased the binding activity of both Sp1 and Sp3 to the 63-bp short COL2A1 promoter, suggesting that the cytokine exerts a post-transcriptional regulatory mechanism on Sp1 and Sp3 gene expressions. Altogether, these data indicate that modulation of Sp3/Sp1 ratio in cartilage could be a potential target to prevent or limit the tissue degradation.Articular cartilage is a highly specialized tissue composed of a complex extracellular matrix of proteoglycans, collagens, and noncollagenous glycoproteins. Cartilage collagens include type II as the major form and types VI, IX, and XI as minor components (1). Type II collagen is an homotrimer composed of ␣1(II) chains encoded by the COL2A1 gene. Previous studies have delineated minimal sequences in the first intron of human, mouse, and rat COL2A1 genes which are sufficient to direct chondrocyte-specific expression in cultured chondrocytes and transgenic mice (2-5). Several binding sites of the intronic enhancer sequences were shown to interact with transcription factors that form chondrocyte-specific complexes, such as SOX9, L-SOX5, and SOX6 (6, 7), and also with factors having less tissue-specific expression, such as Sp1, Sp3, and C-KROX (5, 8). Indeed, promoter sequences are also implicated through interaction with the intronic enhancer sequence, for tissuespecific expression during in vivo and in vitro chondrogenesis (7, 9, 10). In a 266-bp promoter of the human COL2A1 gene mediating enhanced transcription activity, we identified several binding sites for Sp1, Sp3, and C-KROX (5, 8, 11). Sp1 w...

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“…31 Human IL-1b suppresses the synthesis of hyaline-specific type II collagen, and increases the synthesis of fibroblastic type I and III collagens in human chondrocytes. 30 This dedifferentiation process is though to be due, at least in part, to the upregulation of IL-1b, 32 although we could not rule out the possibility that the profile of IL-1b may also relate to the nature of the donor OA cartilage. TGFb is also an important proinflammatory factor in degenerative joint disease.…”

Section: Gene Expression Profiles Of Chondrocytesmentioning

confidence: 93%

“…Interleukin-1b is thought to be one of the major catabolic proinflammatory cytokines relevant to articular destructive diseases. 29,30 It has also been shown to play a major role in the loss of the differentiated chondrocyte phenotype (dedifferentiation), and alters other cartilage destructive processes. 31 Human IL-1b suppresses the synthesis of hyaline-specific type II collagen, and increases the synthesis of fibroblastic type I and III collagens in human chondrocytes.…”

Section: Gene Expression Profiles Of Chondrocytesmentioning

confidence: 99%

Gene expression profiles of human chondrocytes during passaged monolayer cultivation

Lin

Fitzgerald

et al. 2008

Journal Orthopaedic Research

178

149

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Chondrocyte phenotype has been shown to dedifferentiate during passaged monolayer cultivation. Hence, we have investigated the expression profile of 27 chondrocyte-associated genes from both osteoarthritic cartilage tissue and healthy passaged human articular chondrocytes by quantitative real-time PCR. Our results indicate that the gene expression levels of matrix proteins and proteases in chondrocytes from monolayer culture decrease compared with those from cartilage tissue, while monolayer cultured chondrocytes from normal and osteoarthritic cartilage exhibit similar gene expression patterns. However, chondrocytic gene expression profiles were differentially altered at various stages of passage. The expression of the matrix proteins aggrecan, type II collagen, and fibromodulin inversely correlated with increasing passage number, while fibronectin and link protein exhibited a marked increase with passage. The expression of matrix proteinases MMP-3/9/13 and ADAMTS-4/5 decreased with passage, whereas proteinase inhibitors TIMP-2/3 were elevated. The cytokine IL-1 also showed increased expression with monolayer chondrocyte culture, while IGF-1 expression levels were diminished. No significant changes in TGF-b, or the chondrogenic transcription factors Sox-9, c-fos, or c-jun were observed. Our data indicates that cultured chondrocytes undergo dedifferentiation during monolayer culture, although the gene expression level of transcription factors necessary for chondrogenesis remains unchanged. This data may prove important for the future development of more specific and efficacious cultivation techniques for human articular chondrocyte-based therapies. ß

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Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes.

Cited by 369 publications

References 43 publications

Regulation of matrix turnover in meniscal explants: role of mechanical stress, interleukin-1, and nitric oxide

Regulation of matrix turnover in meniscal explants: role of mechanical stress, interleukin-1, and nitric oxide

Sp1 and Sp3 Transcription Factors Mediate Interleukin-1β Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes

Gene expression profiles of human chondrocytes during passaged monolayer cultivation

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