Lipophilic statins prevent matrix metalloproteinase-mediated cartilage collagen breakdown by inhibiting protein geranylgeranylation

Barter, M.J.; Wang, Hui; Lakey, Rachel; Catterall, John B; Cawston, Tim E.; Young, David A.

doi:10.1136/ard.2010.129197

Cited by 38 publications

(31 citation statements)

References 57 publications

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“…Here, we report a significant and apparently dosedependent reduction of PMA-stimulated release of MMP-9 by HUVECs treated with the lipophilic statins simvastatin and atorvastatin, but not by hydrophilic statin pravastatin. Our findings are in line with previous studies showing that simvastatin (Massaro et al 2010;Barter et al 2010;Corpataux et al 2005;Bellosta et al 1998;Luan et al 2003) or atorvastatin (Corpataux et al 2005;Souza-Costa et al 2007a;Souza-Costa et al 2007b) downregulate MMP-9 levels. Moreover, the lack of effects of pravastatin on net MMP-9 levels aligns with those reported by Hurks and colleagues (Hurks et al 2010), thus suggesting that significant differences exist in the effects exerted by different statins.…”

Section: Discussionsupporting

confidence: 95%

“…Moreover, the lack of effects of pravastatin on net MMP-9 levels aligns with those reported by Hurks and colleagues (Hurks et al 2010), thus suggesting that significant differences exist in the effects exerted by different statins. Other studies support the idea that some, but not all statins, may downregulate MMPs, and give further support to the lack of major effects exerted by pravastatin on MMPs levels (Barter et al 2010;Ikeda et al 2000).…”

Section: Discussionmentioning

confidence: 93%

“…Although there is evidence that statins decrease MMPs levels (Barter et al 2010;Bellosta et al 1998;Ikeda et al 2000;Luan et al 2003;Massaro et al 2010), this is the first study to compare the effects of different statins on MMPs/TIMPs balance in PMAstimulated HUVECs. The effects of PMA on HUVECs may reproduce in vitro the effects exerted by atherogenic factors in vivo, especially in terms of MMP-9 induction (Hah and Lee 2003;Massaro et al 2010).…”

Section: Discussionmentioning

confidence: 96%

“…Among other effects, statins were shown to decrease MMPs expression and activities (Kamio et al 2010;Souza-Costa et al 2007a;Souza-Costa et al 2007b;Massaro et al 2010), and there is also experimental evidence that statins downregulate MMPs in different cell types in vitro (Barter et al 2010;Bellosta et al 1998;Ikeda et al 2000;Luan et al 2003;Massaro et al 2010).…”

Section: Introductionmentioning

confidence: 97%

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Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Izidoro-Toledo

Guimaraes

Belo

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Statins exert anti-inflammatory effects and downregulate matrix metalloproteinases (MMPs) expression, thus contributing to restore cardiovascular homeostasis in cardiovascular diseases. We aimed at comparing the effects of different statins (simvastatin, atorvastatin, and pravastatin) on MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios released by human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA). HUVECs were incubated with statins (0.1-10 μM) for 12 h before stimulation with PMA 100 nM. Monolayers were used to perform cell viability assays and the supernatants were collected to determine MMPs and TIMPs levels by gelatin zymography and/or enzyme immunoassay. While treatment with PMA increased MMP-9 and TIMP-1 levels (by 556% and 159%, respectively; both P < 0.05), it exerted no effects on MMP-2 and TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, attenuated PMA-induced increases in MMP-9 levels (P < 0.05). Only atorvastatin decreased baseline MMP-2 levels significantly (P < 0.05). We found no effects on TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, decreased MMP-9/TIMP-1 ratio significantly (both P < 0.05), whereas atorvastatin and pravastatin, but not simvastatin, decreased MMP-2/TIMP-2 ratio significantly (both P < 0.05). Our data support the notion that statins with different physicochemical features exert variable effects on MMP/TIMP ratios (which reflect net MMP activity). Our results suggest that more lipophilic statins (simvastatin and atorvastatin), but not the hydrophilic statin pravastatin, downregulate net MMP-9 activity. However, atorvastatin and pravastatin may downregulate net MMP-2 activity. The clinical implications of the present findings deserve further investigation.

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Section: Discussionsupporting

confidence: 95%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

See 2 more Smart Citations

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Izidoro-Toledo

Guimaraes

Belo

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…vitro and in vivo studies demonstrated that statins inhibit production of inflammatory cytokines induce apoptosis in variety types of cells and inhibit Matrix Metalloproteinase (MMP)-1, -2, -3 and -9 production and activation 4 . Taken together, statins attenuate production of pro-inflammatory cytokines, inhibit MMP activation and induce apoptosis in variety types of cells 5 .…”

Section: Original Articlementioning

confidence: 99%

Simvastatin as a Modulator of Tissue Remodeling through Inhibition of Matrix Metalloproteinase (MMP) Release from Human Lung Fibroblasts

2011

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Background: Statins can regulate the production of pro-inflammatory cytokines and inhibit MMP production or activation in a variety of types of cells. This study evaluated whether statins would inhibit MMP release from human lung fibroblasts, which play a major role in remodeling processes. Methods: This study, using an in-vitro model (three-dimensional collagen gel contraction system), evaluated the effect of cytokines (tumor necrosis factor-α, TNF-a and interleukin-1β, IL-1b) on the MMP release and MMP activation from human lung fibroblasts. Collagen degradation induced by cytokines and neutrophil elastase (NE) was evaluated by quantifying hydroxyproline. Results: In three-dimensional collagen gel cultures (3D cultures) where cytokines (TNF-a and IL-1b) can induce the production of MMPs by fibroblasts, it was found that simvastatin inhibited MMP release. In 3D cultures, cytokines together with NE induced collagen degradation and can lead to activation of the MMP, which was inhibited by simvastatin. Conclusion: Simvastatin may play a role in regulating human lung fibroblast functions in repair and remodeling processes by inhibiting MMP release and the conversion from the latent to the active form of MMP.

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Statin Use and Knee Osteoarthritis Outcomes: A Longitudinal Cohort Study

Veronese

Koyanagi

Stubbs

et al. 2019

Arthritis Care & Research

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Lipophilic statins prevent matrix metalloproteinase-mediated cartilage collagen breakdown by inhibiting protein geranylgeranylation

Cited by 38 publications

References 57 publications

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Simvastatin as a Modulator of Tissue Remodeling through Inhibition of Matrix Metalloproteinase (MMP) Release from Human Lung Fibroblasts

Statin Use and Knee Osteoarthritis Outcomes: A Longitudinal Cohort Study

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