Perturbations in the HDL metabolic pathway predispose to the development of osteoarthritis in mice following long-term exposure to western-type diet

Objective: Recent data suggest that obesity and related metabolic aberrations are associated with ostearthritis (OA) development, a phenomenon that is attributed at least in part to the consumption of lipidrich diets. To date, the molecular mechanisms that govern the lipid-OA connection remain largely unknown. Given the important role of high-density lipoprotein (HDL) in plasma and tissue lipid metabolism, the main purpose of the present study was to investigate the role of HDL metabolism in the pathobiology of OA. Methods: We used apolipoprotein A-I (apoA-I)-/- mice that lack classical apoA-I containing HDL, LCAT-/mice that have only immature HDL and relatively reduced HDL-cholesterol levels and control C57BL16 mice. Mice were placed on chow or western-type (WTD) and monitored for 24 weeks. Knee joints were removed and articular cartilage was isolated for further analyses. Results: The LCAT-/- mice were significantly more sensitive to the development of diet-induced obesity compared to the C57BL16 and apoA-I-/- mice. Morphological, biochemical and molecular analyses revealed that the LCAT-/- obese mice developed OA, while the C57BL/6 mice that were fed WTD did not. Notably, apoA-I-/- mice that received WTD also developed OA although their body-weight gain was similar to their wild-type counterparts. Interestingly, bone marrow from LCAT-/- and apoA-I-/- mice contained significantly increased number of adipocytes, compared to the other groups. Conclusions: Our findings suggest that perturbations in HDL metabolism predispose to OA following chronic insult with WTD and raise the challenging possibility that HDL has a causative relation to OA in patients with metabolic syndrome. (C) 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.