Inhibition of Gsk3β in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway

Miclea, Razvan L.; Siebelt, Michiel; Finos, Livio; Goeman, Jelle J.; Löwik, Clemens W.G.M.; Oostdijk, Wilma; Weinans, Harrie; Wit, Jan M.; Robanus-Maandag, Els C.; Karperien, Marcel

doi:10.1016/j.joca.2011.07.014

Cited by 58 publications

(59 citation statements)

References 42 publications

(34 reference statements)

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“…The canonical Wnt pathway consists of Wnt ligands interacting with the FRIZZLE receptor, inhibiting glycogen synthase kinase (GSK)-3b, and phosphorylation of b-catenin, resulting in b-catenin stabilization, which then enables its transcriptional transactivation together with T-cell factor (TCF)/LEF complex in the nucleus. In adulthood and aging, b-catenin activation is associated with enhanced cartilage ossification and degeneration via augmented MMP levels (39)(40)(41)(42). Furthermore, procatabolic cytokines, such as IL-1b, induce Wnt protein expression, which elicits b-catenin activation (39).…”

Section: Sirt1 Represses Mmp13 Gene Expression 3123mentioning

confidence: 99%

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

et al. 2017

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Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1b, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1b challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1 2/2 presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.-Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes. FASEB J. 31, 3116-3125 (2017). www.fasebj.orgArticular cartilage undergoes age-related degenerative changes leading to the joint disease osteoarthritis (OA). Gradual loss of hyaline joint cartilage during OA is evoked through chronic synovitis, which involves the accumulation of proinflammatory cytokines, as IL1b, TNF-a, and IL6 within the joint (1-5), subsequently leading to a steady increase in matrix metalloproteinases (MMPs) and a disintegrin and MMP with thrombospondin motifs (ADAMTS) proteins, which further promote cartilage destruction (6-12). Recent experimental attempts ABBREVIATIONS: ACAN, aggrecan gene; ADAMTS, a disintegrin and metalloproteinase with thrombospondin-like motifs; BMP, bone morphogenic protein; ChIP, chromatin immunoprecipitation; COL2A1, collagen-2 a-1 gene; FBS, fetal bovine serum; FGF, fibroblast growth factor; GDF, growth differentiation factor; GSK3b, glycogen synthase kinase-3b; hESC, human embryonic stem cell; KO, knockout; LEF, lymphoid enhancer factor; MMP, matrix metalloproteinase; NAM, nicotinamide adenine mononucleotide; OA, osteoarthritis; Res, resveratrol; qPCR, quantitative PCR; siRNA, small interfering RNA; SIRT1, silent mating type information regulation 2 homolog 1 (sirtuin-1); SOX9, sex-determining-region-on-the-Y-chromosome-relate...

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Section: Sirt1 Represses Mmp13 Gene Expression 3123mentioning

confidence: 99%

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

et al. 2017

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“…It is shown that both constitutive up- or downregulation of the canonical Wnt pathway negatively influence cartilage development and maintenance resulting in OA-like features [19]. This suggests that a tight regulation of this signaling cascade is crucial throughout the chondrocyte life cycle.…”

Section: Discussionmentioning

confidence: 99%

Chondroprotective Activity ofMurraya exoticathrough Inhibitingβ-Catenin Signaling Pathway

Liu

Zhang

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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Osteoarthritis (OA) is a degenerative joint disease that affects millions of people. Currently, there is no effective drug treatment for it. The purpose of this study is to investigate the chondroprotective effects of Murraya exotica (L.) on OA. The rat OA models were duplicated to prepare for separating OA chondrocytes, synovial fluid (SF), and serum containing M. exotica (50 mg/kg, 100 mg/kg, and 200 mg/kg), M. exotica showed the activity of decreasing the contents of TNF-α and IL-1β in SF and the chondrocyte apoptosis in a dose-dependent manner. To investigate the probable mechanism, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to determine gene expression and protein profiles, respectively. The results reveal that M. exotica can downregulate mRNA and protein expressions of β-catenin and COX-2 and reporter activity significantly. Conclusively, M. exotica exhibits antiapoptotic chondroprotective activity probably through inhibiting β-catenin signaling.

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“…49 In addition, activation of Wnt signalling by pharmaceutical inhibition of GSK3β increased levels of active (nuclear) β-catenin within the articular cartilage and resulted in cartilage alterations consistent with those seen in early OA, particularly cartilage fibrillation, in a rat model. 60 Conversely, knockdown of the Wnt pathway inhibitor Dkk1 using antisense oligonucleotides protected cartilage and bone in a rat model of OA; 61 however, overexpression of Dkk1 by adenoviral transfer or in chondrocyte-specific Dkk1 transgenic mice also protected the joint in the mouse destabilization of the medial meniscus model of OA. 62 …”

Section: Wnts and Oa: A Challenging Networkmentioning

confidence: 99%

To Wnt or not to Wnt: the bone and joint health dilemma

2013

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The Wnt signalling cascades have essential roles in development, growth and homeostasis of joints and the skeleton. Progress in basic research, particularly relating to our understanding of intracellular signalling cascades and fine regulation of receptor activation in the extracellular space, has provided novel insights into the roles of Wnt signalling in chronic arthritis. Cartilage and bone homeostasis require finely tuned Wnt signalling; both activation and suppression of the Wnt–β-catenin cascade can lead to osteoarthritis in rodent models. Genetic associations with the Wnt antagonist encoded by FRZB and the transcriptional regulator encoded by DOT1L with osteoarthritis further corroborate the essential part played by Wnts in the joint. In rheumatoid arthritis, inhibition of Wnt signalling has a role in the persistence of bone erosions, whereas Wnts have been associated with the ankylosing phenotype in spondyloarthritis. Together, these observations identify the Wnt pathway as an attractive target for therapeutic intervention; however, the complexity of the Wnt signalling cascades and the potential secondary effects of drug interventions targeting them highlight the need for further research and suggest that our understanding of this exciting pathway is still in its infancy.

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Inhibition of Gsk3β in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway

Cited by 58 publications

References 42 publications

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

Chondroprotective Activity ofMurraya exoticathrough Inhibitingβ-Catenin Signaling Pathway

To Wnt or not to Wnt: the bone and joint health dilemma

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