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SAT0006 High Systemic LDL Cholesterol Levels Lead to Synovial Activation and Strongly Accelerate Development of Ectopic Bone Formation During Experimental Osteoarthritis
  1. W. de Munter1,
  2. M.H. van den Bosch1,
  3. S.W. Annet1,
  4. K. Croce2,
  5. N. Hogg3,
  6. T. Vogl4,
  7. J. Roth4,
  8. W.B. van den Berg1,
  9. P.M. van der Kraan1,
  10. P.L. van Lent1
  1. 1Experimental Rheumatology (272), Radboud university medical center, Nijmegen, Netherlands
  2. 2Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Boston, United States
  3. 3Leukocyte Adhesion Laboratory, London Research Institute, London, United Kingdom
  4. 4Institute of Immunology, Muenster, Germany

Abstract

Background A relation between osteoarthritis (OA) and increased cholesterol levels is apparent.

Objectives In the present study we investigate OA pathology in apolipoprotein E-deficient (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 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 36. Joint pathology was investigated by immunohistochemistry and RNA expression and protein production by synovium were determined using RT-PCR and luminex, respectively. Data are depicted as mean ± standard deviation.

Results Although minimal differences in cartilage damage were found between the WT and ApoE-/- mice, an increase in synovial thickening was found in the latter. At end-stage OA, ApoE-/- mice on a standard diet showed increased ectopic bone formation, particularly at the medial collateral ligament, compared to 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 as well as increased levels of the chemokine KC, 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 end point. 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 no increase in KC-levels, suggesting a role for S100-proteins in cholesterol-mediated synovial activation.

Conclusions Increased cholesterol levels result in synovial activation and ectopic bone formation in experimental OA. Excessive LDL levels strongly elevate synovial activation and ectopic bone formation in early-stage collagenase-induced OA.

Disclosure of Interest None declared

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