Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
Department of Stomatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Apr;1870(4):167090. doi: 10.1016/j.bbadis.2024.167090. Epub 2024 Feb 18.
Osteoarthritis (OA) is a complex joint disease that currently has no cure. OA involves metabolic disorders in chondrocytes and an imbalance between autophagy and apoptosis. As a common risk factor for OA, obesity induces changes in the fatty acid composition of synovial fluid, thereby disturbing chondrocyte homeostasis. However, whether unsaturated fatty acids affect the development of OA by regulating chondrocyte autophagy remains unclear. This study aimed to determine the effects of oleic and linoleic acids on chondrocyte autophagy and related mechanisms. Based on the mass spectrometry results, the levels of multiple unsaturated fatty acids, including oleic and linoleic acids, in the synovial fluid of patients with OA and obesity were significantly higher than those in patients with OA only. Moreover, we found that FOXO1 and SIRT1 were downregulated after oleic and linoleic acids treatment of chondrocytes, which inhibited chondrocyte autophagy. Importantly, the upregulation of SIRT1 and FOXO1 expression not only increased the level of autophagy but also improved the expression of chondrocyte extracellular matrix proteins. Furthermore, upregulated SIRT1 and FOXO1 expression alleviated the destruction of the articular cartilage in an OA rat model. Our results suggest that SIRT1/FOXO1 signaling can alleviate oleic acid- and linoleic acid-induced cartilage degradation both in vitro and in vivo and that the SIRT1/FOXO1 pathway may serve as an effective treatment target for inhibiting OA progression.
骨关节炎（OA）是一种复杂的关节疾病，目前尚无治愈方法。OA 涉及软骨细胞的代谢紊乱和自噬与凋亡之间的失衡。肥胖作为 OA 的常见危险因素，会引起滑液中脂肪酸组成的变化，从而扰乱软骨细胞的内稳态。然而，不饱和脂肪酸是否通过调节软骨细胞自噬来影响 OA 的发展尚不清楚。本研究旨在确定油酸和亚油酸对软骨细胞自噬的影响及其相关机制。基于质谱结果，发现 OA 合并肥胖患者的滑液中多种不饱和脂肪酸（包括油酸和亚油酸）的水平明显高于仅 OA 患者。此外，我们发现油酸和亚油酸处理软骨细胞后 FOXO1 和 SIRT1 的表达下调，抑制了软骨细胞自噬。重要的是，上调 SIRT1 和 FOXO1 的表达不仅增加了自噬水平，而且改善了软骨细胞细胞外基质蛋白的表达。此外，上调 SIRT1 和 FOXO1 的表达减轻了 OA 大鼠模型中关节软骨的破坏。我们的结果表明，SIRT1/FOXO1 信号通路可以减轻体外和体内油酸和亚油酸诱导的软骨降解，SIRT1/FOXO1 途径可能成为抑制 OA 进展的有效治疗靶点。
