Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.
Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.
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DOI：
10.1101/gad.934301
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发表时间：
2001-11
影响因子：
10.5
通讯作者：
E. Schipani;H. Ryan;Susanna Didrickson;Tatsuya Kobayashi;M. Knight;R. Johnson
中科院分区：
文献类型：
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作者：
E. Schipani;H. Ryan;Susanna Didrickson;Tatsuya Kobayashi;M. Knight;R. Johnson
血管缺氧是许多常见人类疾病的标志，包括癌症、心肌梗死和中风。哺乳动物组织中缺氧反应的主要介质是转录因子缺氧诱导因子1 （HIF-1）及其氧敏感成分HIF-1 α。围绕hif -1 α和缺氧反应的一个关键问题是该转录因子在从功能血管床移除的细胞中的作用；在这方面，有证据表明它可以作为一种生存因子或诱导生长停滞和细胞凋亡。为了更密切地研究hif -1 α在体内缺氧情况下的功能，我们使用组织特异性靶向方法删除了无血管组织（发育中的骨软骨生长板）中的hif -1 α。我们在这里展示了哺乳动物发育生长板缺氧的第一个证据，并且这种缺氧发生在其内部而不是周围。由于这种发育性缺氧，生长板内部缺乏hif -1 α的细胞死亡。这与HIF-1alpha缺失生长板中CDK抑制剂p57的表达减少和BrdU结合水平增加相结合，表明HIF-1alpha调节的生长停滞在这些动物中发生缺陷。此外，我们发现生长板中VEGF的表达通过hif - 1α依赖性和非依赖性机制进行调节。特别是，我们提供的证据表明，在细胞死亡周围的软骨细胞中，VEGF的表达以hif - 1α独立的方式上调，这反过来诱导异位血管生成。总之，我们的研究结果对缺氧反应和hif -1 α在血管流动中断时组织发育和细胞存活中的作用具有重要意义；它们还说明了体内HIF-1alpha反应的复杂性，并为生长板发育机制提供了新的见解。
Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1alpha. A key question surrounding HIF-1alpha and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1alpha in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.