Background/Purpose:  Synovial macrophages are involved in osteophyte formation during experimental collagenase-induced osteoarthritis (OA). Accumulated LDL can be oxidized in an inflammatory environment such as OA and be taken up by scavenger receptors of macrophages, changing the macrophage fenotype. The effect of LDLr deficiency and cholesterol accumulation on OA pathology was investigated using an experimental OA model.

Methods:  LDLr deficient (LDLr^-/-) mice and their wild type (WT) controls received either a high cholesterol or control diet for 120 days. Experimental OA was induced by intra-articular injection of collagenase on day 84 and 86. Paraffin sections of total knee joints were stained with safranin O – fast green or haematoxylin – eosin to determine OA development. Thickening of the synovial lining layer was measured using an arbitrary scale (0 to 3). Cartilage destruction was determined in four cartilage surfaces of the knee joint (lateral and media femur and tibia) using the OA score developed by Pritzker et al.(2006), adapted by us for mice (0 to 30). Size of osteophyte formation was determined using image analysis by measuring osteophyte surface areas at the margins of the tibial plateau and femoral condyles. Data are depicted as mean ± SD.

Results:  WT mice receiving a normal diet developed moderate cartilage destruction (6.1 ± 2.6), synovial thickening (1.4 ± 0.6), and osteophyte formation (56.5 µm² ± 94.6). Both LDLr^-/- groups showed comparable cartilage destruction and showed no change in bodyweight (23.99 g ± 1.85). WT mice receiving a cholesterol-rich diet showed increased bodyweight compared to the other three groups (28.82 g ± 4.81; p<0.0001), however, no significantly increased cartilage destruction was observed. No differences between the four groups were found regarding synovial thickening. LDL levels were significantly higher in LDLr^-/- mice compared to WT mice (7.33 mmol/L ± 1.44 and 0.54 mmol/L ± 0.11 respectively; p<0.0001), which was additionally increased by a cholesterol-rich diet (38.73 mmol/L ± 9.84; p<0.0001). At the tibial plateau, LDL^-/- mice showed almost a 4 times increase of osteophyte formation compared to WT mice (206.3 µm² ± 196.3; p<0.05). When receiving a cholesterol-rich diet, osteophyte formation at the lateral side of the tibial plateau in LDLr^-/- mice further increased from 107.0 µm² ± 156.0 to 309.4 µm² ± 132.0 (p<0.05).

Conclusion:  Enhanced LDL levels correlate with increased osteophyte formation in LDLr^-/- mice, suggesting a pathologic role of LDL accumulation during OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/low-density-lipoprotein-receptor-deficiency-results-in-osteophyte-formation-during-experimental-osteoarthritis-which-is-enhanced-under-high-cholesterol-conditions/