title: High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis.
abstract: OBJECTIVE
  A relation between osteoarthritis (OA) and increased cholesterol levels is apparent. In the present study we investigate OA pathology in apolipoprotein E (ApoE)(-)(/-) mice with and without a cholesterol-rich diet, a model for high systemic low density lipoprotein (LDL) cholesterol levels independent of weight.
  
  
  METHODS
  Wild type (WT), Apoe(-)(/-), S100a9(-/-) and Apoe(-)(/-)S100a9(-/-) mice (C57BL/6 background) received a standard or cholesterol-rich diet. Experimental OA was induced by intra-articular injection of collagenase and animals were sacrificed at day 10 and day 36.
  
  
  RESULTS
  Although minimal differences in cartilage damage were found between the WT and ApoE(-)(/-) mice, increased synovial thickening was found in the latter. Thirty-six days after OA-induction, ApoE(-)(/-) mice on a standard diet showed increased ectopic bone formation, particularly at the medial collateral ligament, compared with OA in WT mice. Furthermore, a significant increase in synovial gene expression of both S100a8 and S100a9 and S100A8/S100A9 protein levels was found in ApoE(-)(/-) mice, suggesting an activated inflammatory status of synovial cells. In both ApoE(-)(/-) and WT mice, addition of a cholesterol-rich diet resulted in excessive bone formation in the medial collateral ligament at late-time-point OA. Interestingly, at the early time point, proteoglycan deposition was already significantly increased in ApoE(-)(/-) mice compared with WT mice. Mice deficient for both ApoE and S100a9 also showed increased ectopic bone formation, but not synovial activation, suggesting a role for S100-proteins in cholesterol-mediated synovial activation.
  
  
  CONCLUSIONS
  Increased cholesterol levels strongly elevate synovial activation and ectopic bone formation in early-stage collagenase-induced OA.
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Wouter.deMunter@radboudumc.nl.
authors.forename: W
authors.initials: W
authors.lastname: de Munter
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Martijn.vandenBosch@radboudumc.nl.
authors.forename: M H
authors.initials: MH
authors.lastname: van den Bosch
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Annet.Sloetjes@radboudumc.nl.
authors.forename: A W
authors.initials: AW
authors.lastname: Slöetjes
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: KCroce@partners.org.
authors.forename: K J
authors.initials: KJ
authors.lastname: Croce
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany. Electronic address: Vogl@uni-muenster.de.
authors.forename: T
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany. Electronic address: RothJ@uni-muenster.de.
authors.forename: J
authors.initials: J
authors.lastname: Roth
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Marije.Koenders@radboudumc.nl.
authors.forename: M I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Fons.vandeLoo@radboudumc.nl.
authors.forename: F A
authors.initials: FA
authors.lastname: van de Loo
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Wim.vandenBerg@radboudumc.nl.
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Peter.vanderKraan@radboudumc.nl.
authors.forename: P M
authors.initials: PM
authors.lastname: van der Kraan
authors.affiliation: Experimental Rheumatology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address: Peter.vanLent@radboudumc.nl.
authors.forename: P L
authors.initials: PL
authors.lastname: van Lent
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000172:deficiency; D001169:Arthritis, Experimental / Q000097:blood* / Q000150:complications; D040501:Calgranulin A / Q000502:physiology; D040502:Calgranulin B / Q000502:physiology; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D008078:Cholesterol, LDL / Q000097:blood*; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000150:complications; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009999:Ossification, Heterotopic / Q000097:blood* / Q000209:etiology; D010003:Osteoarthritis / Q000097:blood* / Q000150:complications; D013585:Synovitis / Q000097:blood* / Q000209:etiology
chemical_list: D001057:Apolipoproteins E; D040501:Calgranulin A; D040502:Calgranulin B; D002791:Cholesterol, Dietary; D008078:Cholesterol, LDL; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse
keywords: Cholesterol; Inflammation; Low density lipoprotein; Osteophytes; S100A8; S100A9