Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes.

Goldring, Mary B.; Birkhead, James R.; Suen, Lii-Fang; Yamin, Rina; Mizuno, Shota; Glowacki, Julie; Arbiser, Jack L.; Apperley, JF

doi:10.1172/jci117595

Cited by 420 publications

(428 citation statements)

References 61 publications

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“…Nuclear run-on and transient transfection experiments have shown that a IL-1␤ negative signal for human COL2A1 gene transcription involves a 577-bp proximal promoter region and the specific enhancer sequence present in the first intron of the gene (23). Similar effects were also observed in immortalized human articular chondrocytes (24). These data suggest that IL-1␤ exerts its control on type II collagen production through binding sequences of the promoter and/or first intron regions of the COL2A1 gene.…”

mentioning

confidence: 70%

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

119

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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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mentioning

confidence: 70%

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

119

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“…Human chondrocyte cell line C28/I2 was a kind gift from Dr. Mary Goldring (41). The cells were cultured in Dulbecco's modified Eagle's medium (DMEM)/Ham's F-12 (1:1) (Invitrogen), containing 5% fetal bovine serum (FBS) with 100 units/ml penicillin G and 100 g/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

Kakoi

Maeda

Shinohara

et al. 2014

Journal of Biological Chemistry

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Background: It is not clear how BMP-induced chondrocyte maturation is cell-autonomously terminated. Results: BMP-2 induced the ceramide-generating enzyme neutral sphingomyelinase 2 (nSMase2) in chondrocytes, whereas silencing of nSMase2 enhanced maturation in an Akt signaling-dependent manner. Conclusion: nSMase2 signaling regulates BMP-induced chondrocyte maturation as a negative feedback mechanism. Significance: This study elucidated the novel link between BMP and lipid signaling in chondrogenesis.

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“…The co-transfection experiments were also carried out in an immortalized human chondrocyte cell line, C-20/A4 (Figure 3, Goldring et al, 1994). Such a cell line was used because the cellular origin of chondrosarcomas are chondrocytes, thus we were interested in analysing the activity of the fusion proteins in a cellular context resembling as much as possible the one in which they occur in vivo.…”

Section: Transcriptional Activation Of Tec and Ews/tec Isoformsmentioning

confidence: 99%

“…COS-1 cells were maintained in DMEM with 10% FBS and the human chondrocyte cell line C-20/A4 (Goldring et al, 1994) in DMEM/F12 (1 : 1) with 10% FBS. Both culture medium were supplemented with 100 units/ml penicillin G, 100 mg/ml streptomycin sulfate and 0.25 mg/ml amphotericin B.…”

Section: Cell Linesmentioning

confidence: 99%

The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator

et al. 1999

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The EWS/TEC gene fusion generated by the t(9;22) chromosomal translocation found in extraskeletal myxoid chondrosarcomas encodes a fusion protein containing the amino-terminal domain of the EWS protein fused to the whole coding sequence of the orphan nuclear receptor TEC. We have compared the DNA-binding and transcriptional activation properties of various TEC isoforms and the corresponding EWS/TEC fusion proteins. Band-shift experiments show that the fulllength TEC receptor can e ciently bind the NGFI-B Response Element (NBRE), whereas an isoform lacking the entire carboxyl-terminal domain of the receptor binds much less e ciently the NBRE. Addition of the aminoterminal domain of EWS to either isoforms does not alter signi®cantly their DNA-binding properties to the NBRE. Co-transfection experiments of COS cells and human chondrocytes indicate that whereas TEC moderately activates transcription from a NBRE-containing promoter, the corresponding EWS/TEC fusion protein is a highly potent transcriptional activator of the same promoter, being approximately 270-fold more active than the native receptor. EWS/TEC may thus exert its oncogenic potential in chrondrosarcomas by activating the transcription of target genes involved in cell proliferation.

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Interleukin-1 beta-modulated gene expression in immortalized human chondrocytes.

Cited by 420 publications

References 61 publications

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

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

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator

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