UMR 7365 CNRS-Université de Lorraine, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Biopôle de l'Université de Lorraine, 54500 Vandoeuvre-les-Nancy, France.
Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Int J Mol Sci. 2024 Feb 2;25(3):1810. doi: 10.3390/ijms25031810.
Osteoarthritis (OA) is the most prevalent form of arthritis and a major cause of pain and disability. The pathology of OA involves the whole joint in an inflammatory and degenerative process, especially in articular cartilage. OA may be divided into distinguishable phenotypes including one associated with the metabolic syndrome (MetS) of which dyslipidemia and hyperglycemia have been individually linked to OA. Since their combined role in OA pathogenesis remains to be elucidated, we investigated the chondrocyte response to these metabolic stresses, and determined whether a n-3 polyunsaturated fatty acid (PUFA), i.e., eicosapentaenoic acid (EPA), may preserve chondrocyte functions. Rat chondrocytes were cultured with palmitic acid (PA) and/or EPA in normal or high glucose conditions. The expression of genes encoding proteins found in cartilage matrix (type 2 collagen and aggrecan) or involved in degenerative (metalloproteinases, MMPs) or in inflammatory (cyclooxygenase-2, COX-2 and microsomal prostaglandin E synthase, mPGES) processes was analyzed by qPCR. Prostaglandin E (PGE) release was also evaluated by an enzyme-linked immunosorbent assay. Our data indicated that PA dose-dependently up-regulated the mRNA expression of and . PA also induced the expression of and and promoted the synthesis of PGE. Glucose at high concentrations further increased the chondrocyte response to PA. Interestingly, EPA suppressed the inflammatory effects of PA and glucose, and strongly reduced MMP-13 expression. Among the free fatty acid receptors (FFARs), FFAR4 partly mediated the EPA effects and the activation of FFAR1 markedly reduced the inflammatory effects of PA in high glucose conditions. Our findings demonstrate that dyslipidemia associated with hyperglycemia may contribute to OA pathogenesis and explains why an excess of saturated fatty acids and a low level in n-3 PUFAs may disrupt cartilage homeostasis.
骨关节炎（OA）是最常见的关节炎形式，也是疼痛和残疾的主要原因。OA 的病理学涉及整个关节的炎症和退行性过程，尤其是关节软骨。OA 可分为可区分的表型，包括与代谢综合征（MetS）相关的表型，其中血脂异常和高血糖已分别与 OA 相关。由于它们在 OA 发病机制中的共同作用仍有待阐明，我们研究了软骨细胞对这些代谢应激的反应，并确定了一种 n-3 多不饱和脂肪酸（PUFA），即二十碳五烯酸（EPA），是否可以维持软骨细胞的功能。在正常或高葡萄糖条件下，用棕榈酸（PA）和/或 EPA 培养大鼠软骨细胞。通过 qPCR 分析编码软骨基质中发现的蛋白质（II 型胶原和聚集蛋白聚糖）或参与退行性（金属蛋白酶，MMPs）或炎症（环加氧酶-2，COX-2 和微粒体前列腺素 E 合酶，mPGES）过程的基因的表达。还通过酶联免疫吸附测定法评估前列腺素 E（PGE）的释放。我们的数据表明，PA 剂量依赖性地上调了 和 的 mRNA 表达。PA 还诱导了 和 的表达，并促进了 PGE 的合成。高浓度的葡萄糖进一步增加了软骨细胞对 PA 的反应。有趣的是，EPA 抑制了 PA 和葡萄糖的炎症作用，并强烈降低了 MMP-13 的表达。在游离脂肪酸受体（FFARs）中，FFAR4 部分介导了 EPA 的作用，FFAR1 的激活在高葡萄糖条件下显著降低了 PA 的炎症作用。我们的研究结果表明，与高血糖相关的血脂异常可能导致 OA 发病机制，并解释了为什么饱和脂肪酸过多和 n-3 PUFAs 水平低可能会破坏软骨的动态平衡。
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