β-Catenin regulates expression of cyclooxygenase-2 in articular chondrocytes

Kim, Song Ja; Im, Dae Seong; Kim, Seon Hee; Ryu, Je Hwang; Hwang, Sang‐Gu; Seong, Je Kyung; Chun, Churl Hong; Chun, Jaesun

doi:10.1016/s0006-291x(02)00824-0

Cited by 68 publications

(47 citation statements)

References 24 publications

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“…Our results support previous observations regarding the pivotal role LEF1 plays in MMP13 gene expression (21)(22)(23)(24)(25)(26) and add a new facet to our knowledge on LEF1 regulation, which until now had been unknown. A) Superficial zones from articular cartilage of interphalangeal joints (anterior paws) from WT mice ( +/+ ) and Sirt1 2/2 mice were examined for MMP13 and LEF1 levels by immunohistochemistry.…”

Section: Discussionsupporting

confidence: 91%

“…To identify the underlying mechanism by which SIRT1 inhibits MMP13 gene expression, we focused on the LEF1 transcription factor, given that it is implicated in IL-1b-mediated cartilage degeneration in arthritis (21)(22)(23)(24)(25)(26). The transcription factor LEF1 has been shown to positively regulate MMP13 transcription in chondrocytes via an enhancer sequence at the 39 region of the gene (25).…”

Section: The Transcription Factor Lef1 Is a Transactivator Of Mmp13 Amentioning

confidence: 99%

“…Nevertheless, several reports have shown that the Wnt/ b-catenin signaling pathway is involved in IL-1b-mediated cartilage degeneration (21)(22)(23)(24)(25)(26). These studies initially identified a 39 regulatory promoter site of MMP13, to which lymphoid enhancer factor (LEF)-1 binds, thus inducing MMP13 gene expression (25).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 91%

Section: The Transcription Factor Lef1 Is a Transactivator Of Mmp13 Amentioning

confidence: 99%

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

et al. 2017

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“…Increased levels of ␤-catenin have been reported in chondrocytes within areas of degenerative cartilage (26,27). During in vivo ectopic bone formation, bone morphogenetic protein 2 induces ␤-catenin-mediated signaling through Wnt ligands, and ␤-catenin is required for both osteogenesis and chondrogenesis (28).…”

Section: Discussionmentioning

confidence: 99%

Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women

Lane

Nevitt

Lui

et al. 2007

Arthritis & Rheumatism

117

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Objective. To determine whether serum levels of 2 Wnt signaling antagonists, Frizzled-related protein (FRP) and Dkk-1, are associated with the development and progression of radiographic hip osteoarthritis (RHOA).Methods. Pelvic radiographs were obtained a mean of 8.3 years apart in 5,928 Caucasian women >65 years of age who were enrolled in the Study of Osteoporotic Fractures. Random sampling of this cohort was performed, with ϳ180 subjects per group assigned to 2 nested case-control studies on RHOA incidence and progression. Baseline serum levels of FRP and Dkk-1 were measured by capture enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression analyses with adjustment for potential covariates.Results. There were no differences in serum levels of FRP and Dkk-1 between case subjects with incidence or progression of RHOA and their respective control subjects. There was a trend for higher baseline serum levels of FRP to be associated with a reduced risk of incident RHOA ( Conclusion. Elevated circulating levels of Dkk-1 appeared to be associated with reduced progression of RHOA in elderly women, whereas the highest quartile of serum FRP levels tended to be associated with a modest reduction in risk of incident RHOA.

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“…β-Catenin appears to be a strong candidate as one of these factors. Recent data has shown that β-Catenin is highly expressed in osteoarthritic cartilage, suggesting that this signaling molecule may be involved in the pathogenesis of osteoarthritis [Kim et al, 2002].…”

Section: Discussionmentioning

confidence: 99%

Wnt‐mediated regulation of chondrocyte maturation: Modulation by TGF‐β

Dong

Drissi

Chen

et al. 2005

J of Cellular Biochemistry

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Wnt proteins are expressed during limb morphogenesis, yet their role and mechanism of action remains unclear during long bone growth. Wnt expression, effects and modulation of signaling events by BMP and transforming growth factor-beta (TGF-β) were evaluated in chick embryonic chondrocytes. Chondrocyte cell cultures underwent spontaneous maturation with increased expression of colX and this was associated with an increase in the expression of multiple Wnts, including Wnts 4, 5a, 8c, and 9a. Both parathyroid hormone related peptide (PTHrP) and TGF-β inhibited colX, but had disparate effects on Wnt expression. While TGF-β strongly inhibited all Wnts, PTHrP did not inhibit either Wnt8c or Wnt9a and had lesser effects on the expression of the other Wnts. BMP-2 induced colX expression, and also markedly increased Wnt8c expression. Overexpression of β-Catenin and/or T cell factor (TCF)-4 also induced the type X collagen promoter. Overexpression of Wnt8c induced maturation, as did overexpression of β-Catenin. The Wnt8c/β-Catenin maturational effects were enhanced by BMP-2 and inhibited by TGF-β. TGF-β also inhibited activation of the Topflash reporter by β-Catenin, suggesting a direct inhibitory effect since the Topflash reporter contains only β-Catenin binding sequences. In turn β-Catenin inhibited activation of the p3TP-Luc reporter by TGF-β, although the effect was partial. Thus, Wnt/β-Catenin signaling is a critical regulator of the rate of chondrocyte differentiation. Moreover, this pathway is modulated by members of the TGF-β family and demonstrates the highly integrated nature of signals controlling endochondral ossification. J. Cell. Biochem. KeywordsWnt; Chondrocyte; β-Catenin; TGF-βtype X collagen Longitudinal bone growth is a highly regulated process in which chondrocytes complete sequential stages of proliferation, maturation, and hypertrophy marked by a 10-fold increase in type X collagen, and expression of alkaline phosphatase [Hunziker, 1994;Johnson and Tabin, 1997]. Local and systemic factors regulate chondrocyte maturation, and act through multiple independent signaling pathways. Several factors are known to influence the rate of chondrocyte differentiation. Transforming growth factor-beta (TGF-β) and parathyroid hormone related peptide (PTHrP) slow the rate of chondrocyte maturation, while bone morphogenetic proteins (BMPs), thyroid hormone, and retinoic acid stimulate terminal differentiation

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β-Catenin regulates expression of cyclooxygenase-2 in articular chondrocytes

Cited by 68 publications

References 24 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

Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women

Wnt‐mediated regulation of chondrocyte maturation: Modulation by TGF‐β

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