Lipophilic statins prevent matrix metalloproteinase-mediated cartilage collagen breakdown by inhibiting protein geranylgeranylation
- 1Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK
- 2Department of Rheumatology, Medical School, Newcastle University, Newcastle upon Tyne, UK
- 3Department of Medicine, Duke University, Durham, North Carolina, USA
- Correspondence to Dr David A Young, Institute of Cellular Medicine, 4th Floor Cookson Building, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
- Accepted 12 June 2010
- Published Online First 6 August 2010
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.
Funding Action Medical Research.
Ethics approval This study was conducted with the approval of the Newcastle and North Tyneside Health Authority.
Provenance and peer review Not commissioned; externally peer reviewed.