Interleukin-6 Plays an Essential Role in Hypoxia-Inducible Factor 2α-Induced Experimental Osteoarthritic Cartilage Destruction in Mice
Interleukin-6 Plays an Essential Role in Hypoxia-Inducible Factor 2α-Induced Experimental Osteoarthritic Cartilage Destruction in Mice
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DOI：
10.1002/art.30451
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发表时间：
2011-09-01
影响因子：
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通讯作者：
Chun, Jang-Soo
中科院分区：
文献类型：
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作者：
Ryu, Je-Hwang;Yang, Siyoung;Chun, Jang-Soo
客观的。缺氧诱导因子 2 α (HIF-2 α)（由 Epas1 编码）通过调节分解代谢因子基因的表达导致骨关节炎 (OA) 软骨破坏。我们进行这项研究是为了探讨白介素 6 (IL-6) 在 HIF-2 α 介导的小鼠 OA 软骨破坏中的作用。方法。在原代培养的小鼠软骨细胞、人 OA 软骨和小鼠实验 OA 软骨的信使 RNA 和蛋白质水平上测定 HIF-2 α、IL-6 和分解代谢因子的表达。野生型、HIF-2 α 敲低 (Epas1(+/-)) 和 Il6(-/-) 小鼠中的实验性 OA 是由 Epas1 腺病毒关节内注射或内侧半月板不稳定引起的。 IL-6 的作用通过用重组 IL-6 蛋白处理或在有或没有 IL-6 中和抗体的小鼠关节内注射 HIF-2 α 腺病毒 (AdEpas1) 来确定。结果。我们发现Il6是关节软骨细胞中HIF-2α的直接靶基因。 Epas1 和 Il6 在人和小鼠 OA 软骨中均上调，而小鼠中的 HIF-2 α 敲低则导致 Il6 表达和软骨破坏均受到抑制。 IL-6处理增强Mmp3和Mmp13表达；相反，Il6 敲除抑制 HIF-2 α 诱导的 Mmp3 和 Mmp13 上调。将 IL-6 蛋白注射到小鼠膝关节中会引发 OA 软骨破坏，而 IL-6 中和则可阻断 HIF-2 α 诱导的软骨破坏，同时调节 Mmp3 和 Mmp13 的表达。此外，Il6 敲除导致 AdEpas1 诱导的抑制和内侧半月板诱导的软骨破坏的不稳定，以及 Mmp3 和 Mmp13 表达的抑制。结论。我们的研究结果表明，IL-6 通过调节 Mmp3 和 Mmp13 水平，充当 HIF-2 α 诱导的小鼠实验性 OA 软骨破坏的关键介质。
Objective. Hypoxia-inducible factor 2 alpha (HIF-2 alpha) (encoded by Epas1) causes osteoarthritic (OA) cartilage destruction by regulating the expression of catabolic factor genes. We undertook this study to explore the role of interleukin-6 (IL-6) in HIF-2 alpha-mediated OA cartilage destruction in mice.Methods. The expression of HIF-2 alpha, IL-6, and catabolic factors was determined at the messenger RNA and protein levels in primary culture mouse chondrocytes, human OA cartilage, and mouse experimental OA cartilage. Experimental OA in wild-type, HIF-2 alpha knockdown (Epas1(+/-)), and Il6(-/-)mice was caused by intraarticular injection of Epas1 adenovirus or destabilization of the medial meniscus. The role of IL-6 was determined by treating with recombinant IL-6 protein or by injecting HIF-2 alpha adenovirus (AdEpas1) intra-articularly in mice with or without IL-6-neutralizing antibody.Results. We found that Il6 is a direct target gene of HIF-2 alpha in articular chondrocytes. Both Epas1 and Il6 were up-regulated in human and mouse OA cartilage, whereas HIF-2 alpha knockdown in mice led to inhibition of both Il6 expression and cartilage destruction. Treatment with IL-6 enhanced Mmp3 and Mmp13 expression; conversely, Il6 knockdown inhibited HIF-2 alpha-induced up-regulation of Mmp3 and Mmp13. Injection of IL-6 protein into mouse knee joints triggered OA cartilage destruction, whereas IL-6 neutralization led to blocking of HIF-2 alpha-induced cartilage destruction with concomitant modulation of Mmp3 and Mmp13 expression. Moreover, Il6 knockout resulted in inhibition of AdEpas1-induced and destabilization of the medial meniscus-induced cartilage destruction as well as inhibition of Mmp3 and Mmp13 expression.Conclusion. Our findings indicate that IL-6 acts as a crucial mediator of HIF-2 alpha-induced experimental OA cartilage destruction in mice via regulation of Mmp3 and Mmp13 levels.