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. 2004 Jul;63(7):867–869. doi: 10.1136/ard.2003.009746

Simvastatin reduces MMP-3 level in interleukin 1ß stimulated human chondrocyte culture

P Lazzerini 1, P Capecchi 1, F Nerucci 1, A Fioravanti 1, F Chellini 1, M Piccini 1, S Bisogno 1, R Marcolongo 1, P Laghi 1
PMCID: PMC1755052  PMID: 15194586

Abstract

Objectives: Matrix metalloproteinases (MMPs) produced by chondrocytes play a role in the development of cartilage degradation in joint diseases. Moreover, inhibition of MMP secretion by macrophages accumulating in arteriosclerotic plaques would account for the plaque stabilising activity of statins in cardiovascular patients. Recently, simvastatin has been shown to inhibit both developing and established collagen induced arthritis in a murine model. We thus decided to investigate the effect of simvastatin on the production of MMP-3 from cultured interleukin (IL)1 stimulated human chondrocytes.

Methods: Cells from human cartilage, obtained from eight subjects with osteoarthritis undergoing surgery for total hip prostheses, were cultured in the presence of different concentrations of simvastatin (5, 10, and 50 µmol/l) with and without IL1ß (5 ng/ml). MMP-3 level was measured in the culture medium after 48 h of incubation.

Results: IL1ß stimulation of chondrocytes increased MMP-3 concentration in the cultures (from 0.69 (0.09) to 1.94 (0.12) ng/µg protein). Incubation with simvastatin was associated with a dose dependent reduction in MMP-3 increase, both in the presence (–15%, –17%, and –26% with 5, 10, and 50 µmol/l, respectively) and in the absence (–32% with 50 µmol/l) of IL1ß. The inhibiting effect of simvastatin was completely reversed by the addition of mevalonate (100 µmol/l) or farnesol (10 µmol/l).

Conclusions: Our data show that simvastatin, by blocking HMGCoA-reductase and interfering in the prenylation processes, is able to inhibit MMP-3 production from cultured human chondrocytes that have been either unstimulated or stimulated with IL1ß, thus suggesting a possible additional mechanism for statins in counteracting chronic joint disease related cartilage damage.

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Figure 1.

Figure 1

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 Effect of the 48 h incubation with 5, 10, and 50 µmol/l simvastatin (S) and 50 µmol/l S+100 µmol/l mevalonate (M), 50 µmol/l simvastatin + 10 µmol/l farnesol (F), and 50 µmol/l simvastatin + 10 µmol/l geranylgeraniol (G) on 5 ng/ml IL1ß dependent MMP-3 production (expressed as ng/µg protein) from cultured chondrocytes from osteoarthitis patients. All experiments were performed in duplicate. Data are expressed as mean (SD). Baseline sample represents the blank control. Student's t test for paired data (simvastatin treated samples + IL1ß v untreated sample + IL1ß). *p<0.05; **p<0.01; n = 8.

Figure 2.

Figure 2

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 Effect of the 48 h incubation with 50 mmol/l simvastatin (S), 50 µmol/l simvastatin + 100 µmol/l mevalonate (M), 50 µmol/l simvastatin + 10 µmol/l farnesol (F), and 50 µmol/l simvastatin + 10 µmol/l geranylgeraniol (G) on spontaneous MMP-3 production (expressed as ng/µg protein) from cultured chondrocytes from osteoarthitis patients. All experiments were performed in duplicate. Data are expressed as mean (SD). Student's t test for paired data (simvastatin treated samples v untreated sample). *p<0.05; n = 8.

Selected References

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