Neutralization of Interleukin (IL)-6-signaling by antibodies is considered a promising tool for the treatment of osteoarthritis (OA). To gain further insight into this potential treatment, this study investigated the effects of IL-6-signaling and IL-6 neutralization on chondrocyte metabolism and the release of IL-6-signaling-related mediators by human chondrocytes. Chondrocytes were collected from 49 patients with advanced knee/hip OA or femoral neck fracture. Isolated chondrocytes were stimulated with different mediators to analyze the release of IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). The effect of IL-6 and IL-6/sIL-6R complex as well as neutralization of IL-6-signaling on the metabolism was analyzed. OA chondrocytes showed high basal IL-6 production and release, which was strongly negatively correlated with the production of cartilage-matrix-proteins. Chondrocytes produced and released sIL-6R and sgp130. The IL-6/sIL-6R complex significantly increased nitric oxide, prostaglandin E and matrix metalloproteinase 1 production, decreased Pro-Collagen Type II and mitochondrial ATP production, and increased glycolysis in OA chondrocytes. Neutralization of IL-6-signaling by antibodies did not significantly affect the metabolism of OA chondrocytes, but blocking of glycoprotein 130 (gp130)-signaling by SC144 significantly reduced the basal IL-6 release. Although IL-6 trans-signaling induced by IL-6/sIL-6R complex negatively affects OA chondrocytes, antibodies against IL-6 or IL-6R did not affect chondrocyte metabolism. Since inhibition of gp130-signaling reduced the enhanced basal release of IL-6, interfering with gp130-signaling may ameliorate OA progression because high cellular release of IL-6 correlates with reduced production of cartilage-matrix-proteins.

中文翻译：

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IL-6 反式信号传导和高自分泌 IL-6 产生在人骨关节炎软骨细胞代谢中的重要性

通过抗体中和白细胞介素 (IL)-6 信号传导被认为是治疗骨关节炎 (OA) 的有前途的工具。为了进一步了解这种潜在的治疗方法，本研究研究了 IL-6 信号传导和 IL-6 中和对软骨细胞代谢以及人类软骨细胞释放 IL-6 信号传导相关介质的影响。软骨细胞采集自 49 名患有晚期膝/髋 OA 或股骨颈骨折的患者。用不同介质刺激分离的软骨细胞，分析 IL-6、可溶性 IL-6 受体 (sIL-6R) 和可溶性 gp130 (sgp130) 的释放。分析了IL-6和IL-6/sIL-6R复合物以及IL-6信号中和对代谢的影响。 OA 软骨细胞表现出较高的基础 IL-6 产生和释放，这与软骨基质蛋白的产生呈强烈负相关。软骨细胞产生并释放 sIL-6R 和 sgp130。 IL-6/sIL-6R 复合物显着增加一氧化氮、前列腺素 E 和基质金属蛋白酶 1 的产生，减少 II 型原胶原和线粒体 ATP 的产生，并增加 OA 软骨细胞的糖酵解。抗体中和 IL-6 信号传导不会显着影响 OA 软骨细胞的代谢，但 SC144 阻断糖蛋白 130 (gp130) 信号传导显着减少基础 IL-6 释放。尽管 IL-6/sIL-6R 复合物诱导的 IL-6 反式信号转导对 OA 软骨细胞产生负面影响，但针对 IL-6 或 IL-6R 的抗体并不影响软骨细胞代谢。由于 gp130 信号传导的抑制会减少 IL-6 基础释放的增强，因此干扰 gp130 信号传导可能会改善 OA 进展，因为 IL-6 的细胞高释放与软骨基质蛋白的产生减少相关。