Hypoxia promotes the production and inhibits the destruction of human articular cartilage.
Hypoxia promotes the production and inhibits the destruction of human articular cartilage.
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DOI：
10.1002/art.37867
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发表时间：
2013-05
影响因子：
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通讯作者：
B. Thoms;K. Dudek;J. Lafont;C. L. Murphy
中科院分区：
文献类型：
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作者：
B. Thoms;K. Dudek;J. Lafont;C. L. Murphy
目的研究低氧对人关节软骨合成代谢和分解代谢途径的影响，并探讨低氧诱导因子（HIF）在其中的作用。方法正常人关节软骨从一系列的捐助者获得在膝上截肢时，由于肉瘤不涉及关节间隙。新鲜软骨组织外植体和分离的细胞经受缺氧和用白细胞介素-1 α处理。在分离的人软骨细胞上进行细胞转染。结果利用染色质免疫沉淀技术，我们发现缺氧诱导软骨形成是通过HIF-2α直接与主调节基因SOX 9的特定位点结合实现的。重要的是，缺氧也抑制自发的和诱导的破坏人软骨在外植体培养。我们发现抗分解反应主要由HIF-1α介导。与单独缺氧相比，通过耗尽HIF靶向的含脯氨酰羟化酶的蛋白2（PHD-2）来操纵缺氧传感途径进一步增强软骨反应。在猪软骨中观察到类似于人软骨的组织特异性代谢的低血糖调节，但在小鼠软骨中没有观察到。结论人软骨中的软骨细胞对缺氧具有良好的适应性，并利用缺氧调节组织特异性代谢。我们的数据显示，虽然基本调节因子，如SOX 9，是小鼠和人类的关键分子，但它们的控制方式可能不同。这是更重要的，因为它是上游调节因子，如需要直接靶向治疗的好处。HIF特异性羟化酶PHD-2可能是软骨修复的相关靶点。
OBJECTIVE To determine the effects of hypoxia on both anabolic and catabolic pathways of metabolism in human articular cartilage and to elucidate the roles played by hypoxia-inducible factors (HIFs) in these responses. METHODS Normal human articular cartilage from a range of donors was obtained at the time of above-the-knee amputations due to sarcomas not involving the joint space. Fresh cartilage tissue explants and isolated cells were subjected to hypoxia and treatment with interleukin-1α. Cell transfections were performed on isolated human chondrocytes. RESULTS Using chromatin immunoprecipitation, we found that hypoxia induced cartilage production in human tissue explants through direct binding of HIF-2α to a specific site in the master-regulator gene SOX9. Importantly, hypoxia also suppressed spontaneous and induced destruction of human cartilage in explant culture. We found that anticatabolic responses were predominantly mediated by HIF-1α. Manipulation of the hypoxia-sensing pathway through depletion of HIF-targeting prolyl hydroxylase-containing protein 2 (PHD-2) further enhanced cartilage responses as compared to hypoxia alone. Hypoxic regulation of tissue-specific metabolism similar to that in human cartilage was observed in pig, but not mouse, cartilage. CONCLUSION We found that resident chondrocytes in human cartilage are exquisitely adapted to hypoxia and use it to regulate tissue-specific metabolism. Our data revealed that while fundamental regulators, such as SOX9, are key molecules both in mice and humans, the way in which they are controlled can differ. This is all the more important since it is upstream regulators such as this that need to be directly targeted for therapeutic benefit. HIF-specific hydroxylase PHD-2 may represent a relevant target for cartilage repair.