Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone

Guerne, Pierre‐André; Desgeorges, Alain; Jaspar, Jean-Marie; Relić, Biserka; Peter, Robin; Hoffmeyer, Pierre; Dayer, Jean‐Michel

doi:10.1016/s0945-053x(99)00021-9

Cited by 49 publications

(42 citation statements)

References 39 publications

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“…Overall, this ongoing molecular destruction of the cartilage matrix is mainly driven by an increased activity of now partly identified proteases: the matrixmetalloproteinases (MMPs-2, -3, -13, …) and the so called aggrecanases of the ADAMTS-family of proteases (most likely ADAMTS-4 and -5). These enzymes are induced by catabolic cytokines such as IL-1 or TNFα, but also by matrix degradation products (Homandberg et al, 1998;Yasuda et al, 2002) and other non-physiologic stimuli, which the cells are exposed to. Recently, also epigenetic regulation of protease expression was reported in osteoarthritic versus normal articular cartilage (Roach et al, 2005).…”

Section: Il-1ß and Bmps -Interactive Players Of Cartilage Matrix Degrmentioning

confidence: 99%

“…Besides its direct effects IL-1 also induces other cytokines with synergistic effects such as IL-6 and LIF (leukaemia inducing factor) (Fan et al, 2004a;Bender et al, 1990;Geng et al, 1996). IL-6 is in its effects similar to IL-1, but shows an overall weaker potential to inhibit proteoglycan synthesis (Guerne et al, 1999). It is needed for prolonged proteoglycan suppression by IL-1 (Nietfeld et al, 1990) and enhances MMP and aggrecanase expression and activity in articular cartilage (Flannery et al, 2000;Kusano et al, 1998).…”

Section: Interleukin-1 Down-regulates Anabolic and Upregulates Catabomentioning

confidence: 99%

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IL-1ß and BMPs - Interactive players of cartilage matrix degradation and regeneration

Aigner

Söeder²,

Haag³

2006

eCM

101

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Intact human adult articular cartilage is central for the functioning of the articulating joints. This largely depends on the integrity of its extracellular matrix, given the high loading forces during movements in particular in the weight-bearing joints. Unlike the first impression of a more or less static tissue, articular cartilage shows -albeit in the adult organism -a slow tissue turnover. Thus, one of the most important questions in osteoarthritis research is to understand the balance of catabolic and anabolic factors in articular cartilage as this is the key to understand the biology of cartilage maintenance and degeneration.Anabolic and catabolic pathways are very much intermingled in articular cartilage. The balance between anabolism and catabolism is titrated on numerous levels, starting from the mediator-synthesizing cells which express either catabolic or anabolic factors. Also, on the level of the effector cells (i.e. chondrocytes) anabolic and catabolic gene expression compete for a balance of matrix homeostasis, namely the synthesis of matrix components and the expression and activation of matrix-degrading proteases. Also, there are multiple layers of intracellular cross-talks in between the anabolic and catabolic signalling pathways. Maybe the most important lesson from this overview is the notion that the anabolic-catabolic balance as such counts and not so much sufficient net anabolism or limited catabolism alone. Thus, it might be neither the aim of osteoarthritis therapy to foster anabolism nor to knock down catabolism, but the balance of anabolic-catabolic activities as a total needs proper titration and balancing.

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Section: Il-1ß and Bmps -Interactive Players Of Cartilage Matrix Degrmentioning

confidence: 99%

Section: Interleukin-1 Down-regulates Anabolic and Upregulates Catabomentioning

confidence: 99%

IL-1ß and BMPs - Interactive players of cartilage matrix degradation and regeneration

Aigner

Söeder²,

Haag³

2006

eCM

101

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“…Part of the controversy related to these data is probably due to the fact that most of in vitro studies were performed in the absence of sIL-6R. Indeed, levels of membrane-bound IL-6R on chondrocytes are lower compared with those of other cell types such as hepatocytes, and the addition of sIL-6R to IL-6 is required to observe the full effect of the cytokine (30). In this way, the sIL-6R⅐IL-6 complex may partially account for the loss of PG commonly associated with arthritic lesions, because it has been shown to increase aggrecanase-mediated catabolism of PG in articular cartilage (31).…”

mentioning

confidence: 99%

Interleukin-6 (IL-6) and/or Soluble IL-6 Receptor Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes Requires a Decrease of Sp1·Sp3 Ratio and of the Binding Activity of Both Factors to the COL2A1 Promoter

Porée

Kypriotou²,

Chadjichristos³

et al. 2008

Journal of Biological Chemistry

135

106

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Type II collagen is composed of ␣1(II) chains encoded by the COL2A1 gene. Alteration of this cartilage marker is a common feature of osteoarthritis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that needs a soluble form of receptor called sIL-6R to exert its effects in some cellular models. In that case, sIL-6R exerts agonistic action. This mechanism can make up for the partial or total absence of membrane-anchored IL-6 receptors in some cell types, such as chondrocytes. Our study shows that IL-6, sIL-6R, or both inhibit type II collagen production by rabbit articular chondrocytes through a transcriptional control. The cytokine and/or sIL-6R repress COL2A1 transcription by a ؊63/؊35 sequence that binds Sp1⅐Sp3. Indeed, IL-6 and/or sIL-6R inhibit Sp1 and Sp3 expression and their binding activity to the 63-bp promoter. In chromatin immunoprecipitation experiments, IL-6⅐sIL-6R induced an increase in Sp3 recruitment to the detriment of Sp1. Knockdown of Sp1⅐Sp3 by small interference RNA and decoy strategies were found to prevent the IL-6-and/or sIL-6R-induced inhibition of COL2A1 transcription, indicating that each of these Sp proteins is required for down-regulation of the target gene and that a heterotypic Sp1⅐Sp3 complex is involved. Additionally, Sp1 was shown to interact with Sp3 and HDAC1. Indeed, overexpression of a fulllength Sp3 cDNA blocked the Sp1 up-regulation of the 63-bp COL2A1 promoter activity, and by itself, inhibits COL2A1 transcription. We can conclude that IL-6, sIL-6R, or both in combination decrease both the Sp1⅐Sp3 ratio and DNA-binding activities, thus inhibiting COL2A1 transcription. Extracellular matrix (ECM)6 of articular cartilage contains tissue-specific macromolecules including types II, IX, and XI collagens and the large aggregating proteoglycan (PG) aggrecan (1). Type II collagen is the major collagen synthesized by chondrocytes in mature articular cartilage. Each ␣1(II) procollagen chain of the triple helix is encoded by the COL2A1 gene, whose transcription is regulated by DNA elements within both the promoter and the first intron regions (2). Thus, several binding sites of the intronic enhancer were shown to interact with transcription factors such as Sox9, L-Sox5, and Sox6 (3, 4), required for cartilage-specific expression of type II collagen during chondrogenesis in vivo (5), as well as with zinc finger transcription factors Sp1, Sp3, and C-Krox (6, 7). The three latter proteins are also able to bind to several binding sites identified in a 266-bp promoter of the human COL2A1 gene (6 -8). Sp1 was shown to be a strong activator of COL2A1 gene expression via the promoter binding sites, whereas Sp3 was found to prevent the Sp1 up-regulation of the COL2A1 promoter activity by binding to the same cis-acting elements (7).In healthy cartilage, chondrocytes maintain steady-state expression of collagens and PGs and are sensitive to a number of growth factors and cytokines that either enhance or reduce type II collagen synthesis. In osteoarthritis and rheumatoid arthritis, structural...

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“…Nevertheless, in vitro studies demonstrate catabolic effects of IL-6 as this cytokine inhibits PG synthesis in chondrocytes, and this effect is potentiated by addition of soluble IL-6 receptor (sIL-6R) (23,24). Combination treatment with IL-6 and sIL-6R has been shown to enhance aggrecanase-mediated PG depletion in cartilage (25).…”

Section: Il-6mentioning

confidence: 99%

Biochemical Mediators Involved in Cartilage Degradation and the Induction of Pain in Osteoarthritis

Ellman¹,

Yan²,

Chen³

et al. 2012

Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition

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Effects of IL-6 and its soluble receptor on proteoglycan synthesis and NO release by human articular chondrocytes: comparison with IL-1. Modulation by dexamethasone

Cited by 49 publications

References 39 publications

IL-1ß and BMPs - Interactive players of cartilage matrix degradation and regeneration

IL-1ß and BMPs - Interactive players of cartilage matrix degradation and regeneration

Interleukin-6 (IL-6) and/or Soluble IL-6 Receptor Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes Requires a Decrease of Sp1·Sp3 Ratio and of the Binding Activity of Both Factors to the COL2A1 Promoter

Biochemical Mediators Involved in Cartilage Degradation and the Induction of Pain in Osteoarthritis

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