Hypoxia. The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis.
Hypoxia. The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis.
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DOI：
10.1186/ar2568
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发表时间：
2009
影响因子：
4.9
通讯作者：
Paleolog EM
中科院分区：
文献类型：
--
作者：
Muz B;Khan MN;Kiriakidis S;Paleolog EM
充足的氧气和营养物质的供应对于细胞的生存和新陈代谢以及正常的体内平衡至关重要。据推测，组织氧张力的变化会导致多种病理，包括类风湿性关节炎（RA），其中特征性滑膜扩张被认为超过了氧气供应，导致滑膜缺氧和灌注不足的区域。事实上，针对“饥饿”血管组织的治疗方式的想法源于这样的概念：血管形成（血管生成）对于向细胞和组织有效输送氧气至关重要，并且支撑了针对一系列癌症的抗血管生成疗法的发展。对氧张力变化的适应性反应的一个重要且明确的“主调节器”是缺氧诱导因子（HIF），它对氧张力的变化非常敏感。 HIF 转录因子信号级联的激活会导致基因表达的广泛变化，从而使细胞、组织和生物体适应氧合减少。最具特征的缺氧反应基因之一是血管生成刺激血管内皮生长因子，其表达在许多细胞类型（包括RA滑膜细胞）中因缺氧而显着上调。这导致了一个明显的悖论，即丰富的滑膜脉管系统（可能有望将氧气水平恢复到正常）与滑膜缺氧区域一起发生。多项研究表明血管内皮生长因子阻断对关节炎动物模型有效；这些发现表明缺氧可能激活血管生成级联反应，从而促进 RA 的发展。最近的数据还表明，除了激活血管生成之外，缺氧还可能调节 RA 中重要的许多其他特征，例如细胞运输和基质降解。对 HIF 转录家族生物学的了解最终可能会导致开发出旨在干扰这一关键信号通路的疗法，从而调节 RA 等缺氧依赖性病理。
An adequate supply of oxygen and nutrients is essential for survival and metabolism of cells, and consequentially for normal homeostasis. Alterations in tissue oxygen tension have been postulated to contribute to a number of pathologies, including rheumatoid arthritis (RA), in which the characteristic synovial expansion is thought to outstrip the oxygen supply, leading to areas of synovial hypoxia and hypoperfusion. Indeed, the idea of a therapeutic modality aimed at 'starving' tissue of blood vessels was born from the concept that blood vessel formation (angiogenesis) is central to efficient delivery of oxygen to cells and tissues, and has underpinned the development of anti-angiogenic therapies for a range of cancers. An important and well characterized 'master regulator' of the adaptive response to alterations in oxygen tension is hypoxia-inducible factor (HIF), which is exquisitely sensitive to changes in oxygen tension. Activation of the HIF transcription factor signalling cascade leads to extensive changes in gene expression, which allow cells, tissues and organisms to adapt to reduced oxygenation. One of the best characterized hypoxia-responsive genes is the angiogenic stimulus vascular endothelial growth factor, expression of which is dramatically upregulated by hypoxia in many cells types, including RA synovial membrane cells. This leads to an apparent paradox, with the abundant synovial vasculature (which might be expected to restore oxygen levels to normal) occurring nonetheless together with regions of synovial hypoxia. It has been shown in a number of studies that vascular endothelial growth factor blockade is effective in animal models of arthritis; these findings suggest that hypoxia may activate the angiogenic cascade, thereby contributing to RA development. Recent data also suggest that, as well as activating angiogenesis, hypoxia may regulate many other features that are important in RA, such as cell trafficking and matrix degradation. An understanding of the biology of the HIF transcription family may eventually lead to the development of therapies that are aimed at interfering with this key signalling pathway, and hence to modulation of hypoxia-dependent pathologies such as RA.
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