PEP-1-SIRT2-induced matrix metalloproteinase-1 and -13 modulates type II collagen expression via ERK signaling in rabbit articular chondrocytes

Eo, Seong‐Hui; Choi, Soo Young; Kim, Song Ja

doi:10.1016/j.yexcr.2016.09.024

Cited by 10 publications

(9 citation statements)

References 44 publications

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“…Our study has indicated that ERK links SIRT2 and the NAD + treatment-produced changes of the GSH/GSSG ratio, the GCL levels and the Nrf2 activity in our experimental model: first, both SIRT2 siRNA and AGK2 can prevent the NAD + -induced increase in ERK phosphorylation, indicating that SIRT2 mediates the NAD + -induced ERK phosphorylation; and second, ERK inhibition can also significantly attenuate the NAD + -induced increases in the GSH/GSSG ratio and the Nrf2 activity. These findings are consistent with previous reports regarding the regulatory effect of SIRT2 on ERK: SIRT2 overexpression regulated type II collagen expression by activating ERK signaling in rabbit articular chondrocytes (Eo et al, 2016); and SIRT2 modulated neuronal differentiation by enhancing ERK/CREB pathway in mesenchymal stem cells (Jeong and Cho, 2017). There are also studies suggesting that SIRT2 and ERK are mutually regulated: ERK can bind to SIRT2, leading to increased protein levels, stability and activity of SIRT2, while SIRT2 inhibition can also block ERK phosphorylation in HEK 293 cells (Choi et al, 2013).…”

Section: Discussionsupporting

confidence: 93%

SIRT2, ERK and Nrf2 Mediate NAD+ Treatment-Induced Increase in the Antioxidant Capacity of PC12 Cells Under Basal Conditions

Zhang

Hong

Cao

et al. 2019

Front. Mol. Neurosci.

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NAD + (oxidized form of nicotinamide adenine dinucleotide) administration is highly beneficial in numerous models of diseases and aging. It is becoming increasingly important to determine if NAD + treatment may directly increase the antioxidant capacity of cells under basal conditions. In the current study, we tested our hypothesis that NAD + can directly enhance the antioxidant capacity of cells under basal conditions by using PC12 cells as a cellular model. We found that NAD + treatment can increase the GSH/GSSG ratios in the cells under basal conditions. NAD + can also increase both the mRNA and protein level of γ-glutamylcysteine ligase (γ-GCL)—a key enzyme for glutathione synthesis, which appears to be mediated by the NAD + -induced increase in Nrf2 activity. These NAD + -induced changes can be prevented by both SIRT2 siRNA and the SIRT2 inhibitor AGK2. The NAD + -induced changes can also be blocked by the ERK signaling inhibitor U0126. Moreover, the NAD + -induced ERK activation can be blocked by both SIRT2 siRNA and AGK2. Collectively, our study has provided the first evidence that NAD + can enhance directly the antioxidant capacity of the cells under basal conditions, which is mediated by SIRT2, ERK, and Nrf2. These findings have suggested not only the great nutritional potential of NAD + , but also a novel mechanism underlying the protective effects of the NAD + administration in the disease models: the NAD + administration can enhance the resistance of the normal cells to oxidative insults by increasing the antioxidant capacity of the cells.

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Section: Discussionsupporting

confidence: 93%

SIRT2, ERK and Nrf2 Mediate NAD+ Treatment-Induced Increase in the Antioxidant Capacity of PC12 Cells Under Basal Conditions

Zhang

Hong

Cao

et al. 2019

Front. Mol. Neurosci.

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“…Our study has indicated that ERK links SIRT2 and the NAD + treatment-produced changes of the GSH/GSSG ratio, the GCL levels and the Nrf2 activity in our experimental model: First, both SIRT2 siRNA and AGK2 can prevent the NAD + -induced increase in ERK phosphorylation, indicating that SIRT2 mediates the NAD + -induced ERK phosphorylation; and second, ERK inhibition can also significantly attenuate the NAD + -induced increases in the GSH/GSSG ratio and the Nrf2 activity. These findings are consistent with previous reports regarding the linkage between SIRT2 and ERK (Koh, 2012;Sung et al, 2012;Yeung et al, 2015;Eo et al, 2016;Jeong and Cho, 2017). Collectively, our study has suggested the following mechanism underlying the effects of NAD + treatment on the glutathione metabolism ( Figure 8): NAD + treatment produces increased SIRT2 activity that causes ERK activation, leading to increased Nrf2 activity, resulting in increased levels of GCL and glutathione synthesis.…”

Section: Discussionsupporting

confidence: 93%

SIRT2, ERK and Nrf2 mediate NAD+ treatment-induced increase in the antioxidant capacity of differentiated PC12 cells under basal conditions

Zhang

Hong

Cao

et al. 2018

Preprint

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NAD + administration is highly beneficial in numerous models of diseases and aging. It is becoming increasingly important to determine if NAD + treatment may increase directly the antioxidant capacity of cells under basal conditions. In current study we tested our hypothesis that NAD + can enhance directly antioxidant capacity of cells under basal conditions by using differentiated PC12 cells as a cellular model. We found that NAD + treatment can increase the GSH/GSSG ratios in the cells under basal conditions. NAD + can also increase both the mRNA and protein level of -glutamylcysteine ligasea key enzyme for glutathione synthesis, which appears to be mediated by the NAD + -induced increase in Nrf2 activity. These NAD + -induced changes can be prevented by both SIRT2 siRNA and the SIRT2 inhibitor AGK2.The NAD + -induced changes can also be blocked by the ERK signaling inhibitor U0126.Moreover, the NAD + -induced ERK activation can be blocked by both SIRT2 siRNA and AGK2.Collectively, our study has provided the first evidence that NAD + can enhance directly the antioxidant capacity of the cells under basal conditions, which is mediated by SIRT2, ERK, and Nrf2. These findings have suggested not only the great nutritional potential of NAD + , but also a novel mechanism underlying the protective effects of the NAD + administration in the disease models: The NAD + administration can enhance the resistance of the normal cells to oxidative insults by increasing the antioxidant capacity of the cells.

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“…The MMP family contains approximately 28 members, which can be divided into subgroups such as collagenases, gelatinases, and stromelysins. Among them, MMP-1 and MMP-13 are considered to be the major collagenases in chondrocytes during conditions of low inflammation [ 23 , 30 ]. Notably, MMP-13 has 5- to 10-fold greater activity than collagen type II and gelatinase activity that is greater than 44-fold higher than that of MMP-1 [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…It also serves as the predominant system that regulates the production of MMPs, which promote the degeneration of chondrocytes. p38 and ERK play major roles in mediating chondrocyte proliferation, dedifferentiation, inflammation, and related gene expression [ 30 ]. To investigate the involvement of the MAPK cascade in the Ros.…”

Section: Discussionmentioning

confidence: 99%

Rosmarinic acid induces rabbit articular chondrocyte differentiation by decreases matrix metalloproteinase-13 and inflammation by upregulating cyclooxygenase-2 expression

Kim

2017

J Biomed Sci

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BackgroundMatrix metalloproteinases (MMPs) are known to play an important role in the degradation of the extracellular matrix and the pathological progression of osteoarthritis (OA). The natural polyphenolic compound rosmarinic acid (Ros. A) has been shown to suppress the inhibitory activity of matrix metalloproteinases (MMPs). However, the effects of Ros. A on OA have not been investigated.MethodsIn the current study, primary articular chondrocytes were cultured from rabbit articular cartilage and treated with Ros. A. Phenotypic characterization was performed by western blotting to assess specific markers, prostaglandin E2 (PGE2) assays, and alcian blue staining to measure sulfated-proteoglycan production.ResultsWe report that in rabbit articular chondrocytes, Ros. A increased type II collagen, sulfated-proteoglycan, cyclooxygenase-2 (COX-2), and PGE2 production in a dose- and time-dependent manner. Furthermore, Ros. A suppressed the expression of MMP-13. In addition, treatment with Ros A activated extracellular signal-regulated kinase (ERK)-1/2 and p38 kinase signaling pathways. Inhibition of MMP-13 enhanced Ros. A-induced type II collagen expression and sulfated-proteoglycan synthesis but COX-2 and PGE2 production were unchanged. Ros. A-mediated up-regulation of ERK phosphorylation was abolished by the MEK inhibitor, PD98059, which prevented induction of the associated inflammatory response. Inhibition of p38 kinase with SB203580 enhanced the increase in type II collagen expression via Ros. A-mediated down-regulation of MMP-13.ConclusionsResults suggest that ERK-1/2 regulates Ros. A-induced inflammation and that p38 regulates differentiation by inhibiting MMP-13 in rabbit articular chondrocytes.

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PEP-1-SIRT2-induced matrix metalloproteinase-1 and -13 modulates type II collagen expression via ERK signaling in rabbit articular chondrocytes

Cited by 10 publications

References 44 publications

SIRT2, ERK and Nrf2 Mediate NAD+ Treatment-Induced Increase in the Antioxidant Capacity of PC12 Cells Under Basal Conditions

SIRT2, ERK and Nrf2 Mediate NAD+ Treatment-Induced Increase in the Antioxidant Capacity of PC12 Cells Under Basal Conditions

SIRT2, ERK and Nrf2 mediate NAD+ treatment-induced increase in the antioxidant capacity of differentiated PC12 cells under basal conditions

Rosmarinic acid induces rabbit articular chondrocyte differentiation by decreases matrix metalloproteinase-13 and inflammation by upregulating cyclooxygenase-2 expression

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