A WNT/β-catenin negative feedback loop inhibits IL-1β induced mmp expression in human articular chondrocytes

Ma, Bin; Blitterswijk, Clemens A. van; Karperien, M.

doi:10.1016/j.joca.2012.02.177

Cited by 3 publications

(16 citation statements)

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“…Recently we have challenged this pro-catabolic role of Wnt/␤-catenin signaling in human cartilage by revealing an unprecedented species difference in the role of canonical Wnt signaling in the expression of MMP-1, -3, and -13 (9). In human chondrocytes Wnt/␤-catenin signaling is part of a negative feedback loop counteracting IL-1␤-induced MMP expression by a noncanonical inhibitory protein-protein interaction of ␤-catenin with NF-B.…”

Section: Discussionmentioning

confidence: 99%

“…We previously showed that Wnt-3A decreased MMP expression through an inhibitory interaction of ␤-catenin with NF-B p65/RELA in human chondrocytes (9). Therefore, we tested whether TCF4 might also influence NF-B activity.…”

Section: Tcf4 Potentiates Nf-b Signaling In Humanmentioning

confidence: 98%

“…ChondrocytesPreviously, we have shown that knockdown of TCF4 in mouse cells abolished Wnt/␤-catenin-induced MMP expression, indicating that at least in animal models MMPs are direct target genes of TCF/LEF transcription factors (9). To determine whether MMPs are direct target genes of TCF4 transcription factors in human chondrocytes, we analyzed 3000 bp of promoter sequence of the MMP-1 and MMP-13 genes for the presence of consensus WREs.…”

Section: Tcf4 Potentiates Nf-b Signaling In Humanmentioning

confidence: 99%

“…In human cells ␤-catenin inhibits NF-B due to a negative protein-protein interaction with p65 (9). Furthermore, also in human chondrocytes the noncanonical Wnt pathway repressed the expression of cartilage-specific extracellular matrix molecules and might be involved in chondrocyte dedifferentiation during in vitro expansion of primary chondrocytes (9,10). At present and in marked contrast to animal models, a direct role of the canonical Wnt pathway in cartilage degeneration in human has not been identified.…”

mentioning

confidence: 99%

“…In marked contrast, we have recently shown that in human chondrocytes IL-1␤-induced Wnt/␤-catenin signaling is part of a negative feedback loop inhibiting NF-B-mediated MMP expression. In human cells ␤-catenin inhibits NF-B due to a negative protein-protein interaction with p65 (9). Furthermore, also in human chondrocytes the noncanonical Wnt pathway repressed the expression of cartilage-specific extracellular matrix molecules and might be involved in chondrocyte dedifferentiation during in vitro expansion of primary chondrocytes (9,10).…”

mentioning

confidence: 99%

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T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling

Zhong

Blitterswijk

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Tcf4 Potentiates Nf-b Signaling In Humanmentioning

confidence: 98%

Section: Tcf4 Potentiates Nf-b Signaling In Humanmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling

Zhong

Blitterswijk

et al. 2013

Journal of Biological Chemistry

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Celastrol, an NF-κB inhibitor, ameliorates hypercalciuria and articular cartilage lesions in a mouse model of secondary osteoporosis

Liu¹,

Cai²,

Zhang³

et al. 2016

Journal of Pharmacological Sciences

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Notwithstanding compelling contribution of NF-κB to the progression of osteoporosis has been reported, little is known regarding direct inhibition of NF-κB benefiting osteoporosis. In this study, therefore, we evaluated the role of celastrol, an NF-κB inhibitor, in a mouse model of secondary osteoporosis. Animals were divided into three groups as Sham (control), SO (secondary osteoporosis) and SO + CA (secondary osteoporosis treated with celastrol). Significant decreases in body weight and body fat were observed following celastrol treatment in SO group, but leptin levels were much higher. Celastrol also exhibited a significant decrease in urinary calcium excretion. Moreover, other important events were observed after celastrol treatment, covering substantial decrements in serum concentrations of PTH, TRAP-5b, CTX and DPD, improved structure of articular cartilage and cancellous bone (revealed by H&E and safranin-O staining), and significant decline in levels of NF-κB (P65), MMP-1, and MMP-9. These findings demonstrated that celastrol treatment not only improved abnormal lipid metabolism and hypercalciuria in mice subjected to secondary osteoporosis, but also ameliorated articular cartilage lesions. Our results provided evidence of targeted therapy for NF-κB in the clinical treatment of secondary osteoporosis.

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Distinct Effect of TCF4 on the NFκB Pathway in Human Primary Chondrocytes and the C20/A4 Chondrocyte Cell Line

et al. 2014

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Objective:Previous studies indicated a difference in crosstalk between canonical WNT pathway and nuclear factor-κB (NFκB) signaling in human and animal chondrocytes. To assess whether the differences found were dependent on cell types used, we tested the effect of WNT modulation on NFκB signaling in human primary articular chondrocytes in comparison with the immortalized human costal chondrocyte cell line C20/A4.Design:We used gene expression analysis to study the effect of WNT modulation on IL1β-induced matrix metalloproteinase (MMP) expression as well as on WNT and NFκB target gene expression. In addition, we tested the involvement of RelA and TCF4 on activation of the WNT and NFκB pathway by TCF/LEF and NFκB reporter experiments, respectively.Results:We found an inhibitory effect of both induction and inhibition of WNT signaling on IL1β-induced MMP mRNA expression in primary chondrocytes, whereas WNT modulation did not affect MMP expression in C20/A4 cells. Furthermore, TCF/LEF and NFκB reporter activation and WNT and NFκB target gene expression were regulated differentially by TCF4 and RelA in a cell type–dependent manner. Additionally, we found significantly higher mRNA and protein expression of TCF4 and RelA in C20/A4 cells in comparison with primary chondrocytes.Conclusions:We conclude that WNT modulation of NFκB is, at least in part, cell type dependent and that the observed differences are likely because of impaired sensitivity of the NFκB pathway in C20/A4 cells to modulations in WNT signaling. This might be caused by higher basal levels of TCF4 and RelA in C20/A4 cells compared to primary chondrocytes.

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A WNT/β-catenin negative feedback loop inhibits IL-1β induced mmp expression in human articular chondrocytes

Cited by 3 publications

References 0 publications

T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling

T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling

Celastrol, an NF-κB inhibitor, ameliorates hypercalciuria and articular cartilage lesions in a mouse model of secondary osteoporosis

Distinct Effect of TCF4 on the NFκB Pathway in Human Primary Chondrocytes and the C20/A4 Chondrocyte Cell Line

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