Lee Gyuseok, Yang Jiye, Kim Su-Jin, Tran Thanh-Tam, Lee Sun Young, Park Ka Hyon, Kwon Seung-Hee, Chung Ki-Ho, Koh Jeong-Tae, Huh Yun Hyun, Seon Jong-Keun, Kim Hyun Ah, Chun Jang-Soo, Ryu Je-Hwang
Chonnam National University, Gwangju, Republic of Korea.
Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Arthritis Rheumatol. 2025 Feb;77(2):151-162. doi: 10.1002/art.42984. Epub 2024 Sep 29.
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.
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.
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.
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.
骨关节炎（OA）是全球最常见的退行性疾病，尚无切实可行的预防方法，治疗选择也有限。最近，我们团队发现了一种与软骨细胞胆固醇代谢异常相关的、导致OA发病机制的新机制。在本研究中，我们旨在建立人类血脂水平与OA之间的临床联系，评估降胆固醇药物在抑制小鼠OA发展中的有效性，并揭示有效阻碍OA进展的降胆固醇机制。
将五种临床批准的降胆固醇药物（非诺贝特、阿托伐他汀、依折麦布、烟酸和洛美他派）注射到内侧半月板不稳定诱导的OA小鼠膝关节内，或与饮食一起给予这些小鼠，同时给它们喂食2%的高胆固醇饮食。使用微阵列分析确定与胆固醇代谢相关的基因表达。此外，通过关节内注射其抑制剂或腺病毒来探索这些基因的体内功能。
逻辑回归分析证实了基于血脂水平的高脂血症诊断标准与OA发病率之间存在密切关系。在所研究的降胆固醇药物中，非诺贝特对软骨破坏具有最显著的保护作用，这归因于对胆固醇流出至关重要的高密度脂蛋白胆固醇水平升高。值得注意的是，在OA进展过程中，载脂蛋白A1结合蛋白（AIBP）表达下调导致胆固醇流出受到抑制。AIBP的过表达有效抑制OA进展。
我们的结果表明，通过给予非诺贝特或过表达AIBP（两者均诱导胆固醇流出）将胆固醇稳态恢复到正常状态，为OA患者提供了一种有效的治疗选择。
