Enhancement of Intracellular Cholesterol Efflux in Chondrocytes Leading to Alleviation of Osteoarthritis Progression

Abstract

Objective: Osteoarthritis (OA) is the most common degenerative disease worldwide, with no practical means of prevention and limited treatment options. Recently, our group unveiled a novel mechanism contributing to OA pathogenesis in association with abnormal cholesterol metabolism in chondrocytes. In this study, we aimed to establish a clinical link between lipid profiles and OA in humans, assess the effectiveness of cholesterol-lowering drugs in suppressing OA development in mice, and uncover the cholesterol-lowering mechanisms that effectively impede OA progression. Methods: Five clinically approved cholesterol-lowering drugs (fenofibrate, atorvastatin, ezetimibe, niacin, and lomitapide) were injected into the knee joints or administered with diet to mice with OA who underwent destabilization of the medial meniscus induction and were fed a 2% high-cholesterol diet. Gene expression linked to cholesterol metabolism was determined using microarray analysis. Furthermore, the in vivo functions of these genes were explored through intra-articular injection of either its inhibitor or adenovirus. Results: Logistic regression analysis confirmed a close relationship between the diagnostic criteria of hyperlipidemia based on serum lipid levels and OA incidence. Among the cholesterol-lowering drugs examined, fenofibrate exerted the most significant protective effect against cartilage destruction, which was attributed to elevated levels of high-density lipoprotein cholesterol that are crucial for cholesterol efflux. Notably, cholesterol efflux was suppressed during OA progression via down-regulation of apolipoprotein A1–binding protein (AIBP) expression. Overexpression of AIBP effectively inhibits OA progression. Conclusion: Our results suggest that restoration of cholesterol homeostasis to a normal state through administration of fenofibrate or AIBP overexpression, both of which induce cholesterol efflux, offers an effective therapeutic option for patients with OA. © 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.