HIF-1α controls extracellular matrix synthesis by epiphyseal chondrocytes
HIF-1α controls extracellular matrix synthesis by epiphyseal chondrocytes
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DOI：
10.1242/jcs.00385
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发表时间：
2003-05-01
影响因子：
4
通讯作者：
Johnson, RS
中科院分区：
文献类型：
--
作者：
Pfander, D;Cramer, T;Johnson, RS
转录因子 HIF-1α 在低氧张力期间改变基因表达中起着至关重要的作用。在之前的一项研究中，我们证明 HIF-1α 对于体内软骨细胞生长停滞和存活至关重要。为了进一步探讨 HIF-1α 在软骨生物学中的作用，我们对原代骨骺软骨细胞进行了靶向删除 HIF-1α 的研究。在这项研究中，我们证明 HIF-1α 对于调节有氧和无氧条件下的糖酵解是必需的。 HIF-1α 缺失的软骨细胞无法在缺氧微环境中维持 ATP 水平，表明该因子是调节软骨细胞代谢的基本要求。缺氧也显着诱导血管生成因子血管内皮生长因子的合成，并且这种增加在HIF-1α无效突变细胞中消失。在缺氧条件下，缺乏 HIF-1α 转录因子的软骨细胞中聚集蛋白聚糖 mRNA 和蛋白质水平显着降低。有趣的是，缺氧 44 小时后，在野生型细胞中检测到 II 型胶原蛋白水平大幅增加。此外，在缺乏 HIF-1α 的软骨细胞中，低氧条件下 H 型胶原 mRNA 和蛋白质水平显着降低。总之，我们的结果清楚地证明了 RIF-1α 在维持骨骺软骨细胞无氧糖酵解以及细胞外基质合成中的重要性。
The transcription factor HIF-1alpha plays a crucial role in modifying gene expression during low oxygen tension. In a previous study, we demonstrated that HIF-1alpha is essential for chondrocyte growth arrest and survival in vivo. To explore further the role of HIF-1alpha in cartilage biology, we undertook studies with primary epiphyseal chondrocytes with a targeted deletion of HIF-1alpha. In this study, we show that HIF-1alpha is necessary for regulating glycolysis under aerobic and anaerobic conditions. HIF-1alpha-null chondrocytes were unable to maintain ATP levels in hypoxic microenvironments, indicating a fundamental requirement for this factor for the regulation of chondrocyte metabolism. Synthesis of the angiogenic factor vascular endothelial growth factor was also significantly induced by hypoxia, and this increase is lost in HIF-1alpha-null mutant cells. Under hypoxic conditions, aggrecan mRNA and protein levels were significantly reduced in chondrocytes lacking the HIF-1alpha transcription factor. Interestingly, strongly increased type-II collagen protein levels were detected in wild-type cells after 44 hours of hypoxia. In addition, type-H collagen mRNA and protein levels were strongly decreased under low oxygen in chondrocytes lacking HIF-1alpha. In summary, our results clearly demonstrate the importance of RIF-1alpha in maintenance of anaerobic glycolysis, and thereby extracellular matrix synthesis, of epiphyseal chondrocytes.