The objective of this study was to determine if mechanistic target of rapamycin (mTOR) inhibition with or without AMP-activated protein kinase (AMPK) activation can protect against primary, age-related OA. Dunkin-Hartley guinea pigs develop mild primary OA pathology by 5 months of age that progresses to moderate OA by 8 months of age. At 5 months, guinea pigs served as young control (n = 3) or were fed either a control diet (n = 8), a diet enriched with the mTOR-inhibitor rapamycin (Rap, 14 ppm, n = 8), or Rap with the AMPK-activator metformin (Rap+Met, 1000 ppm, n = 8) for 12 weeks. Knee joints were evaluated by OARSI scoring, micro-computed tomography, and immunohistochemistry. Glenohumeral articular cartilage was collected for western blotting. Rap- and Rap+Met-treated guinea pigs displayed lower body weight than control. Rap and Rap+Met inhibited articular cartilage mTORC1 but not mTORC2 signaling. Rap+Met, but not Rap alone, stimulated AMPK. Despite lower body weight and articular cartilage mTORC1 inhibition, Rap- and Rap+Met-treated guinea pigs had greater OA severity in the medial tibial plateau due to articular cartilage structural damage and/or proteoglycan loss. Rap and Rap+Met increased plasma glucose compared to control. Plasma glucose concentration was positively correlated with proteoglycan loss, suggesting hyperglycemic stress after Rap treatment was related to worsened OA. This is the first study to show that Rap induced increase in plasma glucose was associated with greater OA severity. Further, articular cartilage mTORC1 inhibition and bodyweight reduction by dietary Rap and Rap+Met did not appear to protect against primary OA during the prevailing hyperglycemia.

中文翻译：

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雷帕霉素诱导的高血糖与年龄相关性骨关节炎恶化有关

本研究的目的是确定雷帕霉素 (mTOR) 抑制机制靶点在有或没有 AMP 活化蛋白激酶 (AMPK) 激活的情况下是否可以预防与年龄相关的原发性 OA。Dunkin-Hartley 豚鼠在 5 个月大时发展为轻度原发性 OA 病理，到 8 个月大时发展为中度 OA。在 5 个月时，豚鼠作为年轻对照 (n = 3) 或喂食对照饮食 (n = 8)、富含 mTOR 抑制剂雷帕霉素 (Rap, 14 ppm, n = 8) 的饮食或 Rap使用 AMPK 激活剂二甲双胍 (Rap+Met, 1000 ppm, n = 8) 12 周。膝关节通过 OARSI 评分、微型计算机断层扫描和免疫组织化学进行评估。收集盂肱关节软骨用于蛋白质印迹。Rap 和 Rap+Met 处理的豚鼠体重低于对照。Rap 和 Rap+Met 抑制关节软骨 mTORC1 但不抑制 mTORC2 信号传导。Rap+Met，但不是单独的 Rap，刺激了 AMPK。尽管体重和关节软骨 mTORC1 抑制较低，但由于关节软骨结构损伤和/或蛋白多糖损失，Rap 和 Rap+Met 治疗的豚鼠在胫骨平台内侧具有更大的 OA 严重性。与对照相比，Rap 和 Rap+Met 增加了血浆葡萄糖。血浆葡萄糖浓度与蛋白多糖损失呈正相关，表明 Rap 治疗后的高血糖应激与 OA 恶化有关。这是第一项表明 Rap 诱导的血浆葡萄糖增加与更大的 OA 严重程度相关的研究。更远，