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

Kimura, Haruhide; Yukitake, Hiroshi; Suzuki, Hirobumi; Tajima, Yasukazu; Gomaibashi, Koyo; Morimoto, Shinji; Funabashi, Yasunori; Yamada, Kiyofumi; Takizawa, Masayuki

doi:10.1254/jphs.09076fp

Cited by 23 publications

(18 citation statements)

References 38 publications

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“…Recent literatures suggest that IL-1β mediated expression of MMPs has been regulated through the activation of MAPKs including ERK, p38 kinase, and JNK signal transduction molecules [37]. Therefore, we determined whether Wogonin mediate its chondroprotective effects through the suppression of MAPKs by measuring the phosphorylation levels of ERK, JNK and p38 in IL-1β stimulated OA chondrocytes.…”

Section: Resultsmentioning

confidence: 97%

Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes

Khan

Haseeb

Ansari

et al. 2017

Free Radical Biology and Medicine

246

183

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Osteoarthritis (OA), characterized by progressive destruction of articular cartilage, is the most common form of human arthritis. Here, we evaluated the potential chondroprotective and anti-inflammatory effects of Wogonin, a naturally occurring flavonoid, in IL-1β-stimulated human OA chondrocytes and cartilage explants. Wogonin completely suppressed the expression and production of inflammatory mediators including IL-6, COX-2, PGE2, iNOS and NO in IL-1β-stimulated OA chondrocytes. Further, Wogonin exhibits potent chondroprotective potential by switching the signaling axis of matrix degradation from catabolic towards anabolic ends and inhibited the expression, production and activities of matrix degrading proteases including MMP-13, MMP-3, MMP-9, and ADAMTS-4 in OA chondrocytes, and blocked the release of s-GAG and COL2A1 in IL-1β-stimulated OA cartilage explants. Wogonin also elevated the expression of cartilage anabolic factors COL2A1 and ACAN in chondrocytes and inhibited the IL-1β-mediated depletion of COL2A1 and proteoglycan content in the matrix of cartilage explants. The suppressive effect of Wogonin was not mediated through the inhibition of MAPKs or NF-κB activation. Instead, Wogonin induced mild oxidative stress through the generation of ROS and depletion of cellular GSH, thereby modulating the cellular redox leading to the induction of Nrf2/ARE pathways through activation of ROS/ERK/Nrf2/HO-1-SOD2-NQO1-GCLC signaling axis in OA chondrocytes. Molecular docking studies revealed that Wogonin can disrupt KEAP-1/Nrf-2 interaction by directly blocking the binding site of Nrf-2 in the KEAP-1 protein. Genetic ablation of Nrf2 using specific siRNA, significantly abrogated the anti-inflammatory and chondroprotective potential of Wogonin in IL-1β-stimulated OA chondrocytes. Our data indicates that Wogonin exerts chondroprotective effects through the suppression of molecular events involved in oxidative stress, inflammation and matrix degradation in OA chondrocytes and cartilage explants. The study provides novel insights into the development of Nrf2 as a promising candidate and Wogonin as a therapeutic agent for the management of OA.

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Section: Resultsmentioning

confidence: 97%

Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes

Khan

Haseeb

Ansari

et al. 2017

Free Radical Biology and Medicine

246

183

View full text Add to dashboard Cite

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“…IL-1β-induced expression of MMPs has been shown to be mediated by activation of the family of MAPKs including ERK, p38 kinase, and JNK27282930. To evaluate the mechanisms responsible for the F4 mediated suppressive effects, we examined the effects of F4 on MAPK signaling cascade by measuring the phosphorylation levels of ERK, JNK and p38 in IL-1β stimulated OA chondrocytes.…”

Section: Resultsmentioning

confidence: 99%

A wogonin-rich-fraction of Scutellaria baicalensis root extract exerts chondroprotective effects by suppressing IL-1β-induced activation of AP-1 in human OA chondrocytes

Khan¹,

Haseeb²,

Ansari³

et al. 2017

Sci Rep

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Osteoarthritis (OA) is a common joint disorder with varying degrees of inflammation and sustained oxidative stress. The root extract of Scutellaria baicalensis (SBE) has been used for the treatment of inflammatory and other diseases. Here, we performed activity-guided HPLC-fractionation of SBE, identified the active ingredient(s) and investigated its chondroprotective potential. We found that the Wogonin containing fraction-4 (F4) was the most potent fraction based on its ability to inhibit ROS production and the suppression of catabolic markers including IL-6, COX-2, iNOS, MMP-3, MMP-9, MMP-13 and ADAMTS-4 in IL-1β-treated OA chondrocytes. OA chondrocytes treated with F4 in the presence of IL-1β showed significantly enhanced expression of anabolic genes ACAN and COL2A1. In an in vitro model of cartilage degradation treatment with F4 inhibited s-GAG release from IL-1β-treated human cartilage explants. The inhibitory effect of F4 was not mediated through the inhibition of MAPKs and NF-κB activation but was mediated through the suppression of c-Fos/AP-1 activity at transcriptional and post transcriptional levels in OA chondrocytes. Purified Wogonin mimicked the effects of F4 in IL-1β-stimulated OA chondrocytes. Our data demonstrates that a Wogonin-rich fraction of SBE exert chondroprotective effects through the suppression of c-Fos/AP-1 expression and activity in OA chondrocytes under pathological conditions.

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“…The MAPK pathway is comprised of ERK1/2, p38 and the JNK family. Other studies have demonstrated that IL-1β induces the release of MMP3 and MMP13 by articular chondrocytes through the activation of ERK1/2 (9,19,20). On the other hand, the MAPK/ERK pathway is also involved in IL-1β-induced decrease in type II collagen and aggrecan expression in chondrocyte-laden agarose constructs (21).…”

Section: Introductionmentioning

confidence: 96%

“…Previous studies have indicated that the mitogen-activated protein kinase (MAPK) pathway is a fundamental pathway for IL-1β-induced catabolic factor gene transcription in articular chondrocytes (9,(17)(18)(19). The MAPK pathway is comprised of ERK1/2, p38 and the JNK family.…”

Section: Introductionmentioning

confidence: 99%

Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes

Wang

Li²,

Fan

et al. 2011

Int J Mol Med

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Abstract. Interleukin (IL)-1β plays an important role in the pathogenesis of osteoarthritis and catabolic processes in articular cartilage. Growing evidence suggests that ERK1/2 activation is involved in IL-1β-mediated matrix metalloproteinase (MMP) 3, MMP13, type II collagen and aggrecan expression in chondrocytes. To investigate the respective effects and the relationship of ERK1 and ERK2, knockdown of ERK1 and/or ERK2 was performed in human chondrocytes using specific small interfering RNAs (siRNAs), and the cells were treated with IL-1β (10 ng/ml) for 24 h. Uninfected chondrocytes treated with IL-1β (10 ng/ml) were used as a positive control. Other cells cultured without IL-1β or siRNA treatment were used as a negative control. The mRNA levels of MMP3, MMP13, type II collagen and aggrecan were evaluated by quantitative real-time PcR. The protein levels of MMP3 and MMP13 in the culture medium were examined by ELISA. The protein levels of type II collagen, aggrecan, ERK1/2 and phospho-ERK1/2 were evaluated by western blotting. The results indicate that IL-1β enhances MMP3 and MMP13 expression and inhibits type II collagen and aggrecan expression. Activation of the MAPK/ERK pathway was observed. Knockdown of ERK1 or ERK2 significantly reversed these effects to similar degree. combined knockdown of ERK1 and ERK2 displayed synergistic effects. ERK1 and phospho-ERK1 or ERK2 and phospho-ERK2 were inhibited by knockdown of ERK1 or ERK2, respectively. No compensatory effect by up-regulation of the opposite isoform was observed. The combined knockdown suppressed ERK1/2 and phospho-ERK1/2. The data suggest that although inhibition of both ERK1 and ERK2 is more effective, inhibition of either ERK isoform may be sufficient and could be used for novel therapies or as drug targets for pharmacological intervention in cartilage breakdown in osteoarthritis.

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

Cited by 23 publications

References 38 publications

Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes

Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes

A wogonin-rich-fraction of Scutellaria baicalensis root extract exerts chondroprotective effects by suppressing IL-1β-induced activation of AP-1 in human OA chondrocytes

Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes

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