title: Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice--a translational model for atherosclerosis.
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.
authors.affiliation: TNO, , Leiden, The Netherlands.
authors.forename: L M
authors.initials: LM
authors.lastname: Gierman
authors.forename: S
authors.initials: S
authors.lastname: Kühnast
authors.forename: A
authors.initials: A
authors.lastname: Koudijs
authors.forename: E J
authors.initials: EJ
authors.lastname: Pieterman
authors.forename: M
authors.initials: M
authors.lastname: Kloppenburg
authors.forename: G J V M
authors.initials: GJ
authors.lastname: van Osch
authors.forename: V
authors.initials: V
authors.lastname: Stojanovic-Susulic
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: H M G
authors.initials: HM
authors.lastname: Princen
authors.forename: A-M
authors.initials: AM
authors.lastname: Zuurmond
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D053318:Apolipoprotein E3 / Q000235:genetics; D050197:Atherosclerosis / Q000150:complications; D000069059:Atorvastatin; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D002791:Cholesterol, Dietary / Q000009:adverse effects; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications*; D051379:Mice; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000188:drug therapy* / Q000209:etiology*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000924:Anticholesteremic Agents; D053318:Apolipoprotein E3; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002791:Cholesterol, Dietary; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin
keywords: Atherosclerosis; Inflammation; Lipids; Osteoarthritis