Lipophilic statins prevent matrix metalloproteinase-mediated cartilage collagen breakdown by inhibiting protein geranylgeranylation.
OBJECTIVE
To investigate if statins prevent cartilage degradation and the production of collagenases and gelatinases in bovine nasal and human articular cartilage after proinflammatory cytokine stimulation.


METHODS
In a cartilage degradation model, the effects of several statins were assessed by measuring proteoglycan degradation and collagen degradation, while collagenolytic and gelatinolytic activity in culture supernatants were determined by collagen bioassay and gelatin zymography. The production of matrix metalloproteinases (MMPs) in cartilage and chondrocytes were analysed by real-time reverse transcriptase PCR and immunoassay. Cytokine-induced signalling pathway activation was studied by immunoblotting.


RESULTS
Simvastatin and mevastatin significantly inhibited interleukin 1 (IL-1)+oncostatin M (OSM)-induced collagen degradation; this was accompanied with a marked decrease in collagenase and gelatinase activity from bovine nasal cartilage. The cholesterol pathway intermediate mevalonic acid reversed the simvastatin-mediated protection of cartilage degradation, and the expression and production of collagenase (MMP-1 and MMP-13) and gelatinase (MMP-2 and MMP-9). Statins also significantly decreased MMP-1 and MMP-13 expression in human articular cartilage and chondrocytes stimulated with IL-1+OSM, and blocked the activation of critical proinflammatory signalling pathways required for MMP expression. The loss of the isoprenoid intermediate geranylgeranyl pyrophosphate due to statin treatment accounted for the inhibition of MMP expression and signalling pathway activation.


CONCLUSIONS
This study shows, for the first time, that lipophilic statins are able to block cartilage collagen breakdown induced by proinflammatory cytokines, by downregulating key cartilage-degrading enzymes. This demonstrates a possible therapeutic role for statins in acting as anti-inflammatory agents and in protecting cartilage from damage in joint diseases.
Barter
Matt J
MJ
Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
Hui
Wang
W
Lakey
Rachel L
RL
Catterall
John B
JB
Cawston
Tim E
TE
Young
David A
DA
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D018093:Gelatinases / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D053582:Interleukin-1alpha / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000502:physiology*; D008798:Mevalonic Acid / Q000494:pharmacology; D055171:Nasal Cartilages / Q000187:drug effects* / Q000378:metabolism; D053683:Oncostatin M / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013729:Terpenes / Q000378:metabolism; D046509:Tissue Culture Techniques
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053582:Interleukin-1alpha; D013729:Terpenes; D053683:Oncostatin M; C012258:mevastatin; D003094:Collagen; D008148:Lovastatin; D019821:Simvastatin; D017364:Collagenases; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D008798:Mevalonic Acid