Enhancement of intervertebral disc cell senescence by WNT/β‐catenin signaling–induced matrix metalloproteinase expression

Hiyama, Akihiko; Sakai, Daisuke; Risbud, Makarand V.; Tanaka, Masahiro; Arai, Fumiyuki; Abe, Koichiro; Mochida, Joji

doi:10.1002/art.27599

Cited by 130 publications

(154 citation statements)

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“…[1][2][3] We previously analyzed that the Wnt/b-catenin (hereafter Wnt) signaling in the NP cells, and reported that activation of the Wnt signaling suppresses proliferation of NP cells and induces cell senescence, referring to the possibility of it triggering the process of degeneration of the IVDs. 4,5 In addition, we have also shown that MMPs, which are up-regulated by Wnt signaling, cause dedifferentiation of NP cells. 4,5 Corr 6 also demonstrated that Wnt signaling has also been associated with degenerative joint disease and matrix degeneration.…”

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confidence: 85%

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The expression and role of non‐canonical (PKC) signaling in nucleus pulposus cell metabolism

Arai

Hiyama

Sakai

et al. 2012

Journal Orthopaedic Research

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Canonical Wnt/b-catenin (hereafter Wnt) signaling regulates the proliferation and differentiation of various cell types. However, the role of non-canonical signaling including protein kinase C (PKC) signaling has not been investigated in intervertebral disc (IVD) cells. The aim of this study was to elucidate whether the activation of PKC signaling act to modulate Wnt signaling in IVD cells. We performed several reporter assays, real-time reverse transcription polymerase chain reaction (RT-PCR), immunohistochemical and immunofluorescence analyses, and western blot analyses using rat nucleus pulposus (NP) cells. We also examined the cell proliferation and cell cycle distribution under phorbol 12-myristate 13-acetate (PMA) stimulation, a known activator of PKC signaling. We found that NP cells exhibited decreased b-catenin mRNA and protein levels upon stimulation with PMA. PMA treatment promoted proliferation and cell cycle progression in a time-and dose-dependent manner. In addition, activation of the PKC signaling also regulated the expression of aggrecan. Finally, activation by PMA induced the expression of several PKC isoforms in NP cells. It is concluded that activation of PKC signaling might lead to an increase in matrix synthesis and cell proliferation, thereby inhibiting IVD degeneration. Crosstalk in these signaling pathways plays an important role in the regulation of IVD homeostasis. Keywords: intervertebral disc (IVD); PKC signal; Wnt signal; disc degeneration Degenerative changes in the intervertebral disc (IVD) contribute to the development of low back pain. Although the phenotypic character of nucleus pulposus (NP) cells is still not defined, it has been reported that the NP cells synthesize extracellular matrix molecules, including type II collagen and proteoglycans (PG) to maintain IVD homeostasis. This homeostasis is lost in patients with disc diseases, eventually leading to low back pain. The destruction of the NP cells involves a loss of differentiated phenotypes (i.e., dedifferentiation), which is characterized by the cessation of type II collagen expression, and onset of fibroblastic type I collagen expression. A variety of soluble factors are known to cause NP dedifferentiation. One of the best studies is the matrix metalloproteinases (MMPs), which play key factors of IVD degeneration.

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confidence: 85%

“…4,5 In addition, we have also shown that MMPs, which are up-regulated by Wnt signaling, cause dedifferentiation of NP cells. 4,5 Corr 6 also demonstrated that Wnt signaling has also been associated with degenerative joint disease and matrix degeneration.…”

mentioning

confidence: 85%

The expression and role of non‐canonical (PKC) signaling in nucleus pulposus cell metabolism

Arai

Hiyama

Sakai

et al. 2012

Journal Orthopaedic Research

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“…Luciferase reporter plasmids correspond to the following: Sox9BS 3 -Luc contains three tandem 18-base pair Sox9 binding sites (35). Col2-Luc contains the rat Col2a1 promoter and enhancer (36). The luciferase assay was performed using a luciferase assay kit (Promega Corp., Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

Basic Helix-Loop-Helix Transcription Factor Twist1 Inhibits Transactivator Function of Master Chondrogenic Regulator Sox9

Boyer

Naski

2012

Journal of Biological Chemistry

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Background: Twist1 inhibits chondrogenesis through an undefined mechanism. Results: Twist1 binds directly to Sox9 and inhibits both Sox9-dependent gene activation and Sox9 binding to target gene enhancer DNA in chondrogenic cells. Conclusion: Twist1 inhibits Sox9 the transactivator function by impeding its sequence-specific DNA-binding activity. Significance: These findings provide a mechanistic basis for the antichondrogenic activity of Twist1.

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“…In order to confirm these hypotheses, we investigated the expression of β-catenin in articular cartilage from Wistar rats at ages corresponding to human developmental stages of toddler (two weeks old), teenager (four weeks old), young adult (six weeks old) and adult (eight weeks old). Lithium chloride (LiCl), a well-known activator of the Wnt/β-catenin signalling pathway [19][20][21], was applied to the primary chondrocytes to facilitate investigations into β-catenin effects and functional interactions at different developmental stages.…”

Section: Introductionmentioning

confidence: 99%

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

Niu

Wang

Xinghong

et al. 2011

International Orthopaedics (SICOT)

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Purpose The objective of this study was to determine the role of β-catenin in normal postnatal articular cartilage growth and degeneration. Methods We investigated β-catenin gene and protein expression in hip cartilage cells of normal Wistar rats at two, four, six and eight weeks of age by using reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Primary articular chondrocytes from eight week old rats were cultured and treated with LiCl for activation of β-catenin. Collagen X and matrix metalloproteinase 13 (MMP-13) were detected by quantitative RT-PCR and immunofluorescence. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and 5 were detected by quantitative RT-PCR, and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was used for detecting cell apoptosis. Results The highest levels of β-catenin expressions were detected in two week old rats, after which a steady decline was observed over the remaining period of observation (p< 0.05). When primary articular chondrocytes from eight week old rats were treated with LiCl, β-catenin mRNA and protein were induced (p<0.05). Moreover, LiCl-activated β-catenin in chondrocytes was associated with significant concomitant increases in mRNA expression of collagen X and the MMP-13 encoding collagenase 3. Significantly increased mRNA expression of ADAMTS-5 was also seen in primary chondrocytes from eight week old rats after LiCl treatment (p<0.05). The effect was specific to ADAMTS-5 since ADAMTS-4, which has similar proteolytic activity but different aggrecanase activity, was unaffected. Finally, TUNEL staining revealed that LiCl-activated β-catenin signalling led to increased cell apoptotic events in chondrocytes (p<0.05). Conclusions Our findings suggest that normal spatiotemporal patterns and degrees of Wnt/β-catenin signalling are needed to maintain postnatal articular cartilage growth and function. In the early stages of cartilage development, activation of β-catenin signalling is necessary for articular cartilage growth, while in adult cartilage it leads to degeneration and osteoarthritic-like chondrocytes.

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Enhancement of intervertebral disc cell senescence by WNT/β‐catenin signaling–induced matrix metalloproteinase expression

Cited by 130 publications

References 48 publications

The expression and role of non‐canonical (PKC) signaling in nucleus pulposus cell metabolism

The expression and role of non‐canonical (PKC) signaling in nucleus pulposus cell metabolism

Basic Helix-Loop-Helix Transcription Factor Twist1 Inhibits Transactivator Function of Master Chondrogenic Regulator Sox9

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

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