Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado–Soybean Unsaponifiables (ASU)

Gabay, Odile; Gosset, Marjolaine; Levy, A.; Salvat, Colette; Sanchez, Christelle; Pigenet, A.; Sautet, Alain; Jacques, Claire; Bérenbaum, Francis

doi:10.1016/j.joca.2007.06.016

Cited by 59 publications

(54 citation statements)

References 35 publications

(30 reference statements)

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“…Results from this study suggest that the ASU + EGCG combination may exert a COX-independent effect mediated, at least in part, through NF-κB inhibition. Gabay et al (2008) showed ASU alone to decrease MMP-3 and -13 expression, PGE 2 synthesis, as well as prevent NF-κB nuclear translocation and inhibit the ERK1/2 signaling pathway in stressed hyalin chondrocytes [28]. Another study has shown EGCG to inhibit LPS-induced IκBα degradation, NF-κB nuclear translocation, and NF-κB DNA binding activity in bone marrow-derived macrophages (BMMs) [25].…”

Section: Resultsmentioning

confidence: 99%

Expression of pro-inflammatory mediators is inhibited by an avocado/soybean unsaponifiables and epigallocatechin gallate combination

Ownby

Fortuno

et al. 2014

Journal of Inflammation

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BackgroundOsteoarthritis (OA) is characterized by inflammation, joint immobility, and pain. Non-pharmacologic agents modulating pro-inflammatory mediator expression offer considerable promise as safe and effective treatments for OA. We previously determined the anti-inflammatory effect of an avocado/soybean unsaponifiables (ASU) and epigallocatechin gallate (EGCG) combination on prostaglandin E2 (PGE2) production and nuclear factor-kappa B (NF-κB) translocation. The aim of this study was to evaluate the effects of ASU + EGCG on pro-inflammatory gene expression.FindingsArticular chondrocytes from carpal joints of mature horses were pre-incubated for 24 hours with control media alone or ASU (8.3 μg/mL) + EGCG (40 ng/mL), followed by one hour activation with interleukin-1 beta (IL-1β, 10 ng/mL) and tumor necrosis factor-alpha (TNF-α, 1 ng/mL). Total cellular RNA was isolated and real-time PCR performed to measure IL-1β, TNF-α, interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and interleukin-8 (IL-8) gene expression. Intracellular localization of NF-κB was analyzed by immunohistochemistry and Western blot. Pre-treatment with ASU + EGCG significantly (P < 0.001) decreased gene expression of IL-1β, TNF-α, IL-6, COX-2, and IL-8 in cytokine-activated chondrocytes. Western blot and immunostaining confirmed NF-κB translocation inhibition.ConclusionsWe demonstrate that ASU + EGCG inhibits cytokine-induced gene expression of IL-1β, TNF-α, IL-6, COX-2, and IL-8 through modulation of NF-κB. Our results indicate that the activity of ASU + EGCG affects a wide array of inflammatory molecules in addition to decreasing PGE2 synthesis in activated chondrocytes. The responsiveness of chondrocytes to this combination supports its potential utility for the inhibition of joint inflammation.

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Section: Resultsmentioning

confidence: 99%

Expression of pro-inflammatory mediators is inhibited by an avocado/soybean unsaponifiables and epigallocatechin gallate combination

Ownby

Fortuno

et al. 2014

Journal of Inflammation

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“…The MEK1/2 inhibitor PD198306, which blocks ERK activation, also reduced the severity of OA lesions in a rabbit model of OA (30). Furthermore, avocado-soybean unsaponifiables (ASU), which are used to treat OA in Europe, were reported to inhibit IL-1β-induced ERK activation, but not p38 kinase or JNK activation, in chondrocytes in vitro (31). These results suggest that inhibition of ERK activation is sufficient to reduce OA lesions.…”

Section: +mentioning

confidence: 86%

The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death

et al. 2009

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Abstract. In a screening program aimed at discovering anti-osteoarthritis (OA) drugs, we identified an imidazo [5,1-c] [1,4]thiazine derivative, ITZ-1, that suppressed both interleukin-1β (IL-1β)-induced proteoglycan and collagen release from bovine nasal cartilage in vitro and suppressed intra-articular infusion of IL-1β-induced cartilage proteoglycan degradation in rat knee joints. ITZ-1 did not inhibit enzyme activities of various matrix metalloproteinases (MMPs), which have pivotal roles in cartilage degradation, while it selectively inhibited IL-1β-induced production of MMP-13 in human articular chondrocytes (HAC). IL-1β-induced MMP production has been shown to be mediated by extracellular signal-regulated protein kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) family signal transduction molecules. An ERK-MAPK pathway inhibitor (U0126), but not a p38 kinase inhibitor (SB203580) or a JNK inhibitor (SP600125), also selectively inhibited IL-1β-induced MMP-13 production in HAC. Furthermore, ITZ-1 selectively inhibited IL-1β-induced ERK activation without affecting p38 kinase and JNK activation, which may account for its selective inhibition of MMP-13 production. Inhibition of nitric oxide (NO)-induced chondrocyte apoptosis has been another area of interest as a therapeutic strategy for OA, and ITZ-1 also suppressed NO-induced death in HAC. These results suggest that ITZ-1 is a promising lead compound for a disease modifying anti-OA drug program.

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“…Isolation of costal cartilage from KO, or WT 7-day-old mice, and chondrocytes plating were adapted from Gabay et al [17]. Briefly, pieces of costal cartilage were incubated in collagenase 3 mg/mL for 1 h 30 min at 37 °C, carefully isolated from soft tissue in PBS, incubated in collagenase 0.5 mg/mL overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Passages 0 and 1 chondrocytes were used for experiments because cartilage marker genes maintained expression. Monolayer cultures were maintained in culture conditions, as previously described [17], and growth medium was replaced every 3 days. Prior to analysis, cells were rinsed with PBS, trypsinized with Trypsin 0.25%, resuspended in 10 ml of growth medium, and counted with a hemocytometer using trypan blue exclusion assay.…”

Section: Methodsmentioning

confidence: 99%

Sirt1-deficient mice exhibit an altered cartilage phenotype

Gabay¹,

Zaal²,

Sanchez³

et al. 2013

Joint Bone Spine

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Objective We previously demonstrated that Sirt1 regulates apoptosis in cartilage in vitro. Here we attempt to examine in vivo cartilage homeostasis, using Sirt1 total body knockout (KO) mice. Method Articular cartilage was harvested from hind paws of 1-week and 3-week-old mice carrying wild type (WT) or null Sirt1 gene. Knees of Sirt1 haploinsufficient mice also were examined, at 6 months. Joint cartilage was processed for histologic examination or biochemical analyses of chondrocyte cultures. Results We found that articular cartilage tissue sections from Sirt1 KO mice up to 3 weeks of age exhibited low levels of type 2 collagen, aggrecan, and glycosaminoglycan content. In contrast, protein levels of MMP-13 were elevated in the Sirt1 KO mice, leading to a potential increase of cartilage breakdown, already shown in the heterozygous mice. Additional results showed elevated chondrocyte apoptosis in Sirt1 KO mice, as compared to WT controls. In addition to these observations, PTP1b (protein tyrosine phosphatase b) was elevated in the Sirt1 KO mice, in line with previous reports. Conclusion The findings from this animal model demonstrated that Sirt1 KO mice presented an altered cartilage phenotype, with an elevated apoptotic process and a potential degradative cartilage process.

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Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado–Soybean Unsaponifiables (ASU)

Abstract: These results demonstrate that ASU express a unique range of activities, which could counteract deleterious processes involved in OA, such as inflammation.

Cited by 59 publications

References 35 publications

Expression of pro-inflammatory mediators is inhibited by an avocado/soybean unsaponifiables and epigallocatechin gallate combination

Expression of pro-inflammatory mediators is inhibited by an avocado/soybean unsaponifiables and epigallocatechin gallate combination

The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death

Sirt1-deficient mice exhibit an altered cartilage phenotype

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