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Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice—a translational model for atherosclerosis
  1. L M Gierman1,2,
  2. S Kühnast1,3,
  3. A Koudijs1,
  4. E J Pieterman1,
  5. M Kloppenburg2,
  6. G J V M van Osch4,
  7. V Stojanovic-Susulic5,
  8. T W J Huizinga2,
  9. H M G Princen1,
  10. A-M Zuurmond1
  1. 1TNO, Leiden, The Netherlands
  2. 2Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4 Department of Orthopaedics and Department Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
  5. 5Janssen, a division of Johnson & Johnson, Pharmaceutical R&D, Malvern, Pennsylvania, USA
  1. Correspondence to Dr A-M Zuurmond, TNO, Zernikedreef 9, P.O. Box 2215, Leiden 2301 CE, The Netherlands; Anne-Marie.Zuurmond{at}tno.nl

Abstract

Objective Hypercholesterolaemia, a risk factor for atherosclerosis (ATH), has been suggested to have a role in the development of osteoarthritis (OA). To test this hypothesis, the effect of cholesterol and different cholesterol-lowering treatments on OA was investigated in a mouse model resembling human lipoprotein metabolism.

Methods Female ApolipoproteinE*3Leiden.human Cholesteryl Ester Transfer Protein mice received a western-type diet with 0.1% (w/w) cholesterol (LC), 0.3% (w/w) cholesterol alone (HC) or treated with 3 mg/kg/day atorvastatin or 0.3 mg/kg/day ezetimibe. One group remained on chow (control). After 39 weeks, OA grades of the knees and the extent of ATH were determined. Plasma cholesterol levels were measured throughout the study.

Results LC and HC groups developed significantly more OA at the medial side than the control group in a dose-dependent manner. Atorvastatin but not ezetimibe treatment significantly suppressed OA development. As expected, features of ATH were significantly increased in the LC and HC groups compared with the control group and suppressed by atorvastatin (48%) and ezetimibe (55%) treatment. There were significant correlations between the development of OA on the medial side of the joint and cholesterol exposure (r=0.4) or ATH features (r=0.3).

Conclusions Dietary cholesterol and accordingly increased plasma levels play a role in the development of OA. The correlation found between OA, cholesterol and ATH demonstrates that these variables are connected, but indicates the contribution of other ongoing processes in the development of OA. The suppressive effect on OA development of atorvastatin but not of ezetimibe, which had similar cholesterol exposure levels, corroborates these findings.

  • Osteoarthritis
  • Atherosclerosis
  • Lipids
  • Inflammation

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