Diacerein has a weak effect on the catabolic pathway of human osteoarthritis synovial fibroblast--comparison to its effects on osteoarthritic chondrocytes

Álvarez-Soria, M. A.; Herrero‐Beaumont, Gabriel; Sánchez‐Pernaute, Olga; Bellido, M.; Largo, Raquel

doi:10.1093/rheumatology/ken116

Cited by 32 publications

(34 citation statements)

References 46 publications

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“…Further, in equine synoviocytes transduced with an adenoviral vector carrying a coding region for IRAP, MMP13 mRNA expression was significantly lower compared to non-transduced controls 8 . Interestingly, however, one study evaluating diacerein did not detect a significant difference in MMP13 in media of human OA chondrocytes stimulated by rhIL-1β (10 U/ml), but differences in experimental design may account for this discrepancy 9 . Reduction of iNOS mRNA and NO release from bovine chondrocytes 10 , human OA chondrocytes in alginate beads 11 , and LPS-stimulated (1 mg/ml) human OA cartilage 12 have also been observed following application of diacerein/rhein in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

Effective reduction of the interleukin-1β transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin RNA mediated RNA interference influences gene expression of mediators implicated in disease pathogenesis

Santangelo

Bertone

2011

Osteoarthritis and Cartilage

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summary Objective To ascertain a viral vector-based short hairpin RNA (shRNA) capable of reducing the interleukin-1β (IL-1β) transcript in osteoarthritis (OA)-prone chondrocytes and detect corresponding changes in the expression patterns of several critical disease mediators. Methods Cultured chondrocytes from 2-month-old Hartley guinea pigs were screened for reduction of the IL-1β transcript following plasmid-based delivery of U6-driven shRNA sequences. A successful plasmid/shRNA knockdown combination was identified and used to construct an adeno-associated virus serotype 5 (AAV5) vector for further evaluation. Relative real-time reverse transcription polymerase chain reaction (RTPCR) was used to quantify in vitro transcript changes of IL-1β and an additional nine genes following transduction with this targeting knockdown vector. To validate in vitro findings, this AAV5 vector was injected into one knee, while either an equivalent volume of saline vehicle (three animals) or non-targeting control vector (three animals) were injected into opposite knees. Fold differences and subsequent percent gene expression levels relative to control groups were calculated using the comparative CT (2−ΔΔCT) method. Results Statistically significant decreases in IL-1β expression were achieved by the targeting knockdown vector relative to both the mock-transduced control and non-targeting vector control groups in vitro. Transcript levels of anabolic transforming growth factor-β (TGF-β) were significantly increased by use of this targeting knockdown vector. Transduction with this targeting AAV5 vector also significantly decreased the transcript levels of key inflammatory cytokines [tumor necrosis factor-α (TNF-α), IL-2, IL-8, and IL-12] and catabolic agents [matrix metalloproteinase (MMP)13, MMP2, interferon-γ (IFN-γ), and inducible nitrous oxide synthase (iNOS)] relative to both mock-transduced and non-targeting vector control groups. In vivo application of this targeting knockdown vector resulted in a >50% reduction (P= 0.0045) or >90% (P= 0.0001) of the IL-1β transcript relative to vehicle-only or non-targeting vector control exposed cartilage, respectively. Conclusions Successful reduction of the IL-1β transcript was achieved via RNA interference (RNAi) techniques. Importantly, this alteration significantly influenced the transcript levels of several major players involved in OA pathogenesis in the direction of disease modification. Investigations to characterize additional gene expression changes influenced by targeting knockdown AAV5 vector-based diminution of the IL-1β transcript in vivo are warranted.

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Section: Discussionmentioning

confidence: 98%

Effective reduction of the interleukin-1β transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin RNA mediated RNA interference influences gene expression of mediators implicated in disease pathogenesis

Santangelo

Bertone

2011

Osteoarthritis and Cartilage

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“…The neutrophils when performing phagocytosis of MSU induce phagolysosomes which are destabilized by the crystals producing the generation of ROS, cytokine release, proteases, products of arachidonic acid, prostaglandins, and myeloperoxidase [41], triggering membrane disruption and cell death, as well as extracellular trap formation, that are composed of loosened chromatin and granule proteins such as neutrophil elastase, cathepsin G, and lactotransferrin. An active cell death mechanism is distinct from apoptosis and necrosis and depends on the production of ROS by NADPH oxidase, Schorn et al in 2012 identified neutrophils, eosinophils, and basophils as capable to externalize nuclear DNA after incubation with MSU [42].…”

Section: Oxidative Stress Mechanisms In Goutmentioning

confidence: 99%

Molecular basis of oxidative stress in gouty arthropathy

et al. 2015

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Gout is a disorder of urate metabolism in which persistent high urate levels in the extracellular fluids result in the deposition of monosodium urate (MSU) crystal in joints and periarticular tissues. In recent years, this disease represents an increasingly common health problem, so the pace of investigation in the field has accelerated tremendously. New research advances in the pathogenesis of hyperuricemia and in the understanding of how MSU crystals induce an acute gouty attack have been focused in this review on the processes of inflammation and involvement of the innate immune response; in addition, we discuss new knowledge about the role of the reactive oxygen species in establishing oxidative stress in MSU crystal-induced arthritis.

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“…Surprisingly, diacerein inhibited IL-1β-stimulated NF-κB activation in synoviocytes and chondrocytes, but increased cyclooxygenase-2 (COX-2) protein expression and PGE 2 synthesis [Pelletier et al 1998;Sanchez et al 2003;Alvarez-Soria et al 2008]. The impact of this PGE 2 overexpression induced by diacerein needs to be clarified, particularly on joint tissue neovascularization.…”

Section: Nsaidsmentioning

confidence: 99%

Targeting the synovial angiogenesis as a novel treatment approach to osteoarthritis

Henrotin

Pesesse

Lambert

2013

Therapeutic Advances in Musculoskeletal

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Synovitis is a key feature in osteoarthritis and is associated with symptom severity. Synovial membrane inflammation is secondary to cartilage degradation which occurs in the early stage and is located adjacent to cartilage damage. This inflammation is characterized by the invasion and activation of macrophages and lymphocytes, the release in the joint cavity of large amounts of pro-inflammatory and procatabolic mediators, and by a local increase of synovial membrane vascularity. This latter process plays an important role in the chronicity of the inflammatory reaction by facilitating the invasion of the synovium by immune cells. Therefore, synovial membrane angiogenesis represents a key target for the treatment of osteoarthritis. This paper is a narrative review of the literature referenced in PubMed during the past 5 years. It addresses in particular three questions. What are the mechanisms involved in synovium blood vessels invasion? Are current medications effective in controlling blood vessels formation and invasion? What are the perspectives of research in this area?

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Diacerein has a weak effect on the catabolic pathway of human osteoarthritis synovial fibroblast--comparison to its effects on osteoarthritic chondrocytes

Abstract: Diacerein does not seem to reduce but rather increase inflammatory mediators in synoviocytes, while it does not overall affect chondrocyte inflammatory profile.

Cited by 32 publications

References 46 publications

Effective reduction of the interleukin-1β transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin RNA mediated RNA interference influences gene expression of mediators implicated in disease pathogenesis

Effective reduction of the interleukin-1β transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin RNA mediated RNA interference influences gene expression of mediators implicated in disease pathogenesis

Molecular basis of oxidative stress in gouty arthropathy

Targeting the synovial angiogenesis as a novel treatment approach to osteoarthritis

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