REGULATION OF COLLAGEN GENE EXPRESSION BY PROSTAGLANDINS AND INTERLEUKIN-1β IN CULTURED CHONDROCYTES AND FIBROBLASTS

Goldring, Mary B.; Suen, Lii-Fang; Yamin, Rina; Lai, Wen‐Fu Thomas

doi:10.1097/00045391-199601000-00003

Cited by 56 publications

(51 citation statements)

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“…To date, 4 receptor subtypes for PGE 2 (PGE 2 subtype receptors 1-4), which are coupled to different second messenger pathways and are responsible for catabolic and anabolic effects, can be distinguished (2,45). Thus, it has been possible to demonstrate that PGE 2 and PGF 2 also have direct stimulatory effects on type II collagen gene expression in chondrocytes and on expression of the chondrogenic factor bone morphogenetic protein 2 (4,5,(46)(47)(48). These observations may explain the more intense staining for mPGES-1 and HIF-1␣ observed in chondrocyte clusters, which are characterized by considerable anabolic activity.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Grimmer¹,

Pfander²,

Swoboda³

et al. 2007

Arthritis & Rheumatism

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Objective. To investigate crosslinks between catabolic and anabolic pathways in articular cartilage by examining the synthesis and distribution pattern of microsomal prostaglandin E synthase 1 (mPGES-1) in healthy and osteoarthritic (OA) cartilage and analyzing its functional relationship to hypoxia-inducible factor 1␣ (HIF-1␣) in primary articular chondrocytes.Methods. Normal cartilage and OA cartilage were subjected to immunohistochemical staining for mPGES-1 and HIF-1␣. Isolated chondrocytes were cultivated under 21% or 1% O 2 . Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction were used to detect genes differentially expressed in chondrocytes cultured under normoxic compared with hypoxic conditions. Immunoblotting was conducted to evaluate intracellular protein levels of mPGES and nuclear accumulation of HIF-1␣ under different oxygen tension levels and with different stimulatory or inhibitory chemical agents.Results. We found enhanced levels of expression of the mPGES-1 gene and an increased number of OA chondrocytes showing staining for mPGES-1 in OA cartilage. Microarray analysis demonstrated that mPGES-1 was among the genes that were up-regulated to the greatest degree in primary chondrocytes exposed to 1% O 2 . In vitro, hypoxia led to an enhanced synthesis of mPGES-1, coinciding with a nuclear accumulation of the transcription factor HIF-1␣. In chondrocyte culture, stimulation with dimethyloxaloylglycine promoted the expression of mPGES-1, phosphoglycerate kinase 1, and cyclooxygenase 2 (COX-2) by stabilizing HIF-1␣ protein levels. A reduction of mPGES-1 synthesis was detected after treatment with 2-methoxyestradiol, correlating with lower HIF-1␣ activity. In contrast, synthesis of mPGES-1 was not influenced by treatment with the specific COX-2 inhibitor NS398.Conclusion. These findings suggest that the transcription factor HIF-1␣ is involved in the up-regulation of mPGES-1 and may therefore play an important role in the metabolism of OA cartilage.The regulation of the metabolism of articular cartilage involves a complex network of a multitude of signaling pathways. In osteoarthritis (OA), the usually well-regulated maintenance between extracellular matrix synthesis and degradation is greatly disturbed. Inflammatory cytokines promote catabolism by inducing expression of matrix-degrading enzymes, which lead to the breakdown of the collagen network and the release of cartilage proteoglycans (1). The biologic effects of interleukin-1␤ (IL-1␤), one of the key agents in the pathophysiology of OA, are mediated by signaling pathways involving NF-B, JNK, p38, or ERK, by nitric oxide, and by cytokines as well as by prostaglandins (2). Prostaglandin E 2 (PGE 2 ), the most abundant prostaglandin in the skeletal system (3), induces a number of matrix-degrading enzymes, thus stimulating the cataboSupported by the Interdisciplinary Center of Clinical Research Erlangen (Project C2) and the DFG (PF 383/4-1).

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Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Grimmer¹,

Pfander²,

Swoboda³

et al. 2007

Arthritis & Rheumatism

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“…This down-regulation involves DNA regulatory sequences that control that gene expression (22). 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).…”

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confidence: 87%

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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“…IL-1␤ also stimulates prostaglandin E 2 (PGE 2 ) production by up-regulation of cyclooxygenase 2 (COX-2), which may worsen symptoms of OA (3,4). On the other hand, stimulation of PGE 2 production by IL-1␤ is also reported to up-regulate type II collagen transcription (5), making the net effect of changes in PGE 2 production complex to determine.…”

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confidence: 99%

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E₂– and cAMP‐dependent pathways in osteoarthritic chondrocytes

Bonnelye¹,

Reboul²,

Duval³

et al. 2011

Arthritis & Rheumatism

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Objective. We reported previously that the orphan nuclear receptor, estrogen receptor-related receptor ␣ (ERR␣), is expressed in articular chondrocytes and is dysregulated in a mouse model of inflammatory arthritis. The aim of this study, therefore, was to determine whether ERR␣ is also dysregulated in patients with osteoarthritis (OA).Methods. ERR␣ messenger RNA (mRNA) and protein were quantified in normal and OA cartilage samples and in OA chondrocytes in vitro, with and without short-term treatment with a variety of OAassociated factors and signaling pathway agonists and inhibitors.Results. ERR␣ expression was lower in OA than in normal articular cartilage. Interleukin-1␤ (IL-1␤) markedly up-regulated ERR␣ expression in OA chondrocytes in vitro, and agonist or inhibitor treatment indicated that the up-regulation was dependent on cyclooxygenase 2 (COX-2; NS398), prostaglandin E 2 , cAMP (8-bromo-cAMP), and protein kinase A (PKA; KT5720). Treatment with the ERR␣ inverse agonist XCT790 decreased the expression of SOX9 and the up-regulation of ERR␣ by IL-1␤, suggesting autoregulation of ERR␣ in the IL-1␤ pathway. Matrix metalloproteinase 13 (MMP-13) expression was also decreased by treatment with XCT790 plus IL-1␤ versus IL-1␤ alone, and the down-regulation of MMP-13 mRNA and protein observed with XCT790 alone suggests that the up-regulation of MMP-13 by IL-1␤ is ERR␣-dependent.Conclusion. We report the first evidence that ERR␣ expression is regulated by IL-1␤ in COX-2-, cAMP-, and PKA-dependent pathways in OA chondrocytes. We confirmed that SOX9 is an ERR␣ target gene in human, as in rodent, chondrocytes and identified MMP-13 as a potential new target gene, which suggests that ERR␣ may both respond to the healing signal and contribute to extracellular degradation in OA cartilage.Osteoarthritis (OA) is a chronic disease characterized by slowly progressive destruction of the articular cartilage, combined with changes in the synovium and subchondral bone (1). Various estimates suggest that more than 40% of 70-year-old people currently have the disease, ranking OA as the most common arthritic condition. The prevalence and the pain and disability associated with progression of the disease have led to intense interest in defining markers for OA as well as the mechanisms underlying the disease.The cellular component of cartilage is the chondrocyte, and adult articular chondrocytes, although considered quiescent in normal cartilage, can respond to mechanical injury and biologic stimuli such as cytokines and growth factors. Interleukin-1␤ (IL-1␤) is a wellknown proinflammatory cytokine that is implicated in

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REGULATION OF COLLAGEN GENE EXPRESSION BY PROSTAGLANDINS AND INTERLEUKIN-1β IN CULTURED CHONDROCYTES AND FIBROBLASTS

Cited by 56 publications

References 0 publications

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

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

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E₂– and cAMP‐dependent pathways in osteoarthritic chondrocytes

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REGULATION OF COLLAGEN GENE EXPRESSION BY PROSTAGLANDINS AND INTERLEUKIN-1β IN CULTURED CHONDROCYTES AND FIBROBLASTS

Cited by 56 publications

References 0 publications

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

Hypoxia‐inducible factor 1α is involved in the prostaglandin metabolism of osteoarthritic cartilage through up‐regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes

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

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E2– and cAMP‐dependent pathways in osteoarthritic chondrocytes

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Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E₂– and cAMP‐dependent pathways in osteoarthritic chondrocytes