STIMULATION OF BMP-2 EXPRESSION BY PRO-INFLAMMATORY CYTOKINES IL-1 AND TNF-α IN NORMAL AND OSTEOARTHRITIC CHONDROCYTES

Fukui, Naoshi; Zhu, Yong; Maloney, William J.; Clohisy, John C.; Sandell, Linda J.

doi:10.2106/00004623-200300003-00011

Cited by 216 publications

(197 citation statements)

References 19 publications

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“…Both show largely similar effects on chondrocyte anabolism as well as phenotype stabilization. In contrast to BMP-2, which appears to be increased in OA cartilage (Fukui et al, 2003), BMP-7 activity is, however, down-regulated in this condition (Merrihew et al, 2003a): whether this is one reason for the enhanced cartilage degeneration in OA needs further investigations.…”

Section: Bone Morphogenetic Proteins Up-regulate Anabolic Activity Ofmentioning

confidence: 89%

“…Though these results are under debate (Glasson et al, 2005), an interesting question is: what could be the molecular mechanism for a potentially beneficial effect of IL-1 on articular cartilage? Recently, Sandell and colleagues were able to show that IL-1ß and TNFα are potent inducers of BMP-2 expression, whereas the anabolic cytokines TGFß and IGF had no effect on the synthesis of BMP-2 (Fukui et al, 2003) (fig. 4).…”

Section: Is Il-1 Important For the Homeostasis Of Articular Cartilage?mentioning

confidence: 99%

“…Maybe the most important lesson of this overview might be the notion that it is the balance, as such, which counts and not so much sufficient net anabolism or limited catabolism alone. (Reproduced with kind permission from Fukui et al 2003) Central to the matter, might be the interwoven dynamics of the anabolic-catabolic balance, possibly suggestedmost intriguingly -by the effects of IL-1 on articular cartilage. A pure increase of anabolism and pure blockage of catabolism might not be the ultimate goal of OA therapy.…”

Section: The Anabolic -Catabolic Balance In Articular Cartilage -Finamentioning

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: Bone Morphogenetic Proteins Up-regulate Anabolic Activity Ofmentioning

confidence: 89%

Section: Is Il-1 Important For the Homeostasis Of Articular Cartilage?mentioning

confidence: 99%

Section: The Anabolic -Catabolic Balance In Articular Cartilage -Finamentioning

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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“…BMPs were originally identified as factors that can induce new bone formation when ectopically implanted, 35 and their roles in cartilage and bone development have been studied extensively. 36 Several studies have shown that TNF-a and/or IL-1b stimulate the expression of Cell-specific effects of TNF-a on TNAP P Lencel et al BMP-2 by chondrocytes, 37,38 suggesting that entheseal inflammation in AS may induce the local secretion of BMP-2, leading to syndesmophyte formation. The putative interest of targeting BMPs in AS has been suggested by Lories and collaborators, who showed that overexpression of noggin, a BMP antagonist with broad BMP ligand interaction, inhibits both the onset and severity of disease in the DBA/1 model of spondyloarthropathy, in a preventive and therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Cell-specific effects of TNF-α and IL-1β on alkaline phosphatase: implication for syndesmophyte formation and vascular calcification

Lencel

Delplace

Pilet

et al. 2011

Laboratory Investigation

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Tumor necrosis factor (TNF)-a and interleukin (IL)-1b stimulate tissue non-specific alkaline phosphatase (TNAP) activity and mineralization in cultures of vascular smooth muscle cells (VSMCs). They are, therefore, considered as stimulators of vascular calcification in the context of atherosclerosis and diabetes type 2. In contrast, although ankylosing spondylitis (AS) leads to the formation of syndesmophytes, which are ectopic ossifications from entheses (where ligaments, tendons and capsules are attached to bone), anti-TNF-a therapies fail to block bone formation in this disease. In this context, our aims were to compare the effects of TNF-a and IL-1b on TNAP activity and mineralization in entheseal cells and VSMCs. Organotypic cultures of mouse ankle entheses were treated or not with TNF-a and IL-1b for 5 days. Micro-computed tomography was performed to determine trabecular bone parameters, and histology to assess TNAP activity and mineralization. Human mesenchymal stem cells cultured in pellets in chondrogenic conditions and human VSMCs were also used to determine the effects of cytokines on TNAP activity and expression, measured by quantitative PCR. In organotypic cultures, TNF-a and IL-1b significantly reduced the tibia BV/TV ratio. They also inhibited TNAP activity in entheseal chondrocytes in situ, and in mouse and human chondrocytes in vitro. In contrast, TNF-a stimulated TNAP expression and activity in human VSMCs. These differences were likely due to cell-specific effects of peroxisome proliferator-activated receptor g (PPARg), which is inhibited by TNF-a. Indeed, in human chondrocytes and VSMCs, the PPARg inhibitor GW-9662 displayed the same opposite effects as TNF-a on TNAP expression. In conclusion, whereas TNF-a and IL-1b stimulate TNAP activity in VSMCs, they inhibit it in entheseal cells in situ and on chondrocytes in vitro. The identification of PPARg as a likely mediator of cytokine effects deserves consideration for future research on the mechanisms of ectopic ossification.

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“…Studies of gene expression in normal and OA cartilage have shown up-regulation of MMP-13 in late-stage OA, whereas MMP-3 is downregulated (8). In addition, bone morphogenetic protein 2 is increased in OA cartilage and colocalizes with newly synthesized type II procollagen, which suggests that anabolic remodeling of the tissue is taking place (9).…”

mentioning

confidence: 99%

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

Lee

Fitzgerald

DiMicco

et al. 2005

Arthritis & Rheumatism

199

172

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Objective. Joint injury in young adults leads to an increased risk of developing osteoarthritis (OA) later in life. This study was undertaken to determine if injurious mechanical compression of cartilage explants results in changes at the level of gene transcription that may lead to subsequent degradation of the cartilage.Methods. Cartilage was explanted from the femoropatellar groove of newborn calves. Levels of messenger RNA encoding matrix molecules, proteases, their natural inhibitors, transcription factors, and cytokines were assessed in free swelling control cultures as compared with cartilage cultures at 1, 2, 4, 6, 12, and 24 hours after application of a single injurious compression.Results. Gene-expression levels measured in noninjured, free swelling cartilage varied over 5 orders of magnitude. Matrix molecules were the most highly expressed of the genes tested, while cytokines, matrix metalloproteinases (MMPs), aggrecanases (ADAMTS-5), and transcription factors showed lower expression levels. Matrix molecules showed little change in expression after injurious compression, whereas MMP-3 increased ϳ250-fold, ADAMTS-5 increased ϳ40-fold, and tissue inhibitor of metalloproteinases 1 increased ϳ12-fold above the levels in free swelling cultures. Genes typically used as internal controls, GAPDH and ␤-actin, increased expression levels ϳ4-fold after injury, making them unsuitable for use as normalization genes in this study. The expression levels of tumor necrosis factor ␣ and interleukin-1␤, cytokines known to be involved in the progression of OA, did not change in the chondrocytes after injury. Conclusion.Changes in the level of gene expression after mechanical injury are gene specific and time dependent. The quantity of specific proteins may be altered as a result of these changes in gene expression, which may eventually lead to degradation at the tissue level and cause a compromise in cartilage structure and function.

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STIMULATION OF BMP-2 EXPRESSION BY PRO-INFLAMMATORY CYTOKINES IL-1 AND TNF-α IN NORMAL AND OSTEOARTHRITIC CHONDROCYTES

Cited by 216 publications

References 19 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

Cell-specific effects of TNF-α and IL-1β on alkaline phosphatase: implication for syndesmophyte formation and vascular calcification

Mechanical injury of cartilage explants causes specific time‐dependent changes in chondrocyte gene expression

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