OP0090 LDL receptor deficiency results in osteophyte formation during experimental osteoarthritis which is increased under high cholesterol conditions
Authors: W. de Munter, B. Walgreen, M.M. Helsen, A.W. Sloetjes, W.B. van den Berg, P.L. van Lent
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Synovial macrophages have previously shown to be involved in joint destruction during experimental collagenase-induced osteoarthritis (OA). The low density lipoprotein (LDL) receptor expressed by synovial macrophages is involved in transport of cholesterol, carrying lipoprotein particles into cells, thereby regulating cholesterol homeostasis. <h3>Objectives</h3> In the present study we investigated whether the LDL receptor is involved in joint destruction during experimental osteoarthritis both under normal and high cholesterol conditions. <h3>Methods</h3> LDL receptor deficient (LDLR<sup>-/-</sup>) mice and their wild type (WT) controls received either a high cholesterol or control diet for 120 days. Experimental osteoarthritis was induced by injection of collagenase into the mice's knee joints on day 84 and 86. Paraffin sections of total knee joints were stained with safranin-o or haematoxylin-eosin to determine OA development. Synovial activation (thickening of the lining layer) was measured using an arbitrary scale from 0 to 3. Cartilage destruction was determined in four cartilage surfaces (lateral and medial femur and tibia) using the OA score (with a maximum of 30 per knee joint) developed by Pritzker <i>et al</i> (2006) and adapted by our lab for mice. Size of osteophyte formation was measured on the edges of the femur/tibia area using image analysis. Results are depicted as mean ± SD. <h3>Results</h3> We first investigated the role of the LDLR under normal cholesterol conditions. On day 36 after induction of collagenase-induced OA, WT mice receiving a normal diet (n=10) developed moderate synovial activation (1.4±0.6), cartilage destruction (6.1±2.6) and osteophyte formation (32.4±25.4 μm<sup>2</sup>). In LDLR<sup>-/-</sup> mice (n=10) no significant differences were found on synovial activation or cartilage destruction when compared to WT controls. In contrast, mean osteophyte formation was strongly increased by 345% suggesting that the absence of the LDL receptor induces osteophyte formation in the OA knee joint. Next, the role of the LDLR under high cholesterol conditions was investigated. On day 36 after OA induction, the bodyweight of WT mice receiving a high cholesterol diet (n=10) had increased by 21% compared to WT mice which received a normal diet. Although synovial activation and cartilage destruction was not altered, osteophyte formation was over 33 times higher (p=0.0495) in the medial femur of the high cholesterol group. LDLR<sup>-/-</sup> mice which received a high cholesterol diet (n=10) expressed high cholesterol levels (500% higher when compared to WT) within the serum and a significantly increased thickening of the lining layer consisting of macrophages containing high amounts of fat as seen after staining of total knee joints with red oil. Although the OA knee joints of WT mice already showed increased osteophyte formation, the OA knee joints of LDLR<sup>-/-</sup> developed even higher osteophyte formation (2.7 times higher in the in the lateral tibia; p=0.0063) indicating that the absence of the LDL receptor also induces osteophyte formation under high cholesterol conditions. <h3>Conclusions</h3> Our data suggest that LDLR deficiency causes osteophyte formation during collagenase-induced osteoarthritis in mice, which is even more pronounced under high cholesterol conditions. <h3>Disclosure of Interest</h3> None Declared