High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis

ObjectiveA 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.MethodWild 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.ResultsAlthough 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.ConclusionsIncreased cholesterol levels strongly elevate synovial activation and ectopic bone formation in early-stage collagenase-induced OA.