Article Text

A9.13 systemic LDL cholesterol-accumulation during experimental oa leads to increased synovial thickening, s100a8/9 production and ectopic bone formation
  1. Wouter de Munter,
  2. Martijn HJ van den Bosch,
  3. Annet W Sloetjes,
  4. Thomas Vogl,
  5. Johannes Roth,
  6. Peter M van der Kraan,
  7. Wim B van den Berg,
  8. Peter LEM van Lent
  1. Department of Experimental Rheumatology, Radboud University Medical Center, The Netherlands; Institut für Immunologie, Muenster, Germany


Introduction In a previous study, we showed that LDL accumulation by LDL receptor deficient mice resulted in increased ectopic bone formation during experimental osteoarthritis (OA). Furthermore, we found that S100A8/A9 proteins are crucial in mediating joint pathology during experimental OA. In the present study we investigate OA pathology and its correlation with S100A8/9 in ApoE-/- mice, which is a different model for studying effects of systemically high LDL cholesterol levels.

Material and Methods Wild type (WT) and ApoE deficient (ApoE-/-) mice received a normal or cholesterol-rich diet for 54 days. At day 18, experimental OA was induced by intra-articular injection of collagenase and animals were sacrificed at day 28 and 54.

Results ApoE-/- mice on a normal diet showed remarkably higher LDL levels than WT mice (8.90 mmol/L and 0.40 mmol/L, respectively; p<0.0001). Experimental OA in ApoE-/- mice showed no increase in synovial thickening and ectopic bone formation, but a significant increase of cartilage damage was found in ApoE-/- mice compared to WT mice at the lateral side of the femoral chondyle (OARSI score 13.7 and 6.8, respectively; p<0.05). Synovial gene expression of both S100A8 and S100A9 was significantly increased in ApoE-/- mice compared to WT mice (fold increase 1.8 and 1.4, respectively; p<0.05). Furthermore, S100A8/S100A9 protein levels of synovial wash-outs was increased in ApoE-/- mice at day 28 (fold increase 5.8; p<0.05), which was confirmed by immunohistochemical staining for S100A8.

In addition, we investigated whether a cholesterol-rich diet could increase joint pathology after induction of OA. This diet increased differences in LDL levels even more (18.4 mmol/L in ApoE-/- mice versus 1.2 mmol/L in WT mice; p<0.0001) and already at day 28, histological differences between the two groups were observed. Synovial thickening was increased by 400% in ApoE-/- mice compared to WT mice (p<0.001) and also ectopic bone formation in the medial collateral ligament was strongly increased at this early time point (fold increase 2.7; p<0.01). Cartilage damage, however, was comparable to damage observed in mice on a normal diet. Again, S100A8 and S100A9 levels were strongly increased in ApoE-/- mice, both on protein and gene expression level and significantly correlated with ectopic bone formation.

Conclusion LDL cholesterol accumulation by ApoE deficiency results in increased S100A8 and S100A9 production by synovial cells. A cholesterol-rich diet further increases this production which correlates with increased synovial thickening and ectopic bone formation in experimental OA. This suggests a important role for LDL cholesterol in developing OA joint pathology.

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