Regulation of hypoxia-inducible factor-1α (HIF-1α) expression by interleukin-1β (IL-1 β), insulin-like growth factors I (IGF-I) and II (IGF-II) in human osteoarthritic chondrocytes.
Regulation of hypoxia-inducible factor-1α (HIF-1α) expression by interleukin-1β (IL-1 β), insulin-like growth factors I (IGF-I) and II (IGF-II) in human osteoarthritic chondrocytes.
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DOI：
10.6061/clinics/2012(01)06
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Coimbra IB
中科院分区：
文献类型：
--
作者：
Sartori-Cintra AR;Mara CS;Argolo DL;Coimbra IB
缺氧诱导因子1 α调节缺氧条件下细胞存活相关基因。该因子存在于骨关节炎软骨细胞中，并且细胞因子如白细胞介素-1 β参与骨关节炎的发病机制，从而增加蛋白水解酶如基质金属蛋白酶的活性，并加速软骨破坏。我们假设缺氧诱导因子-1 α（HIF-1α）可以调节骨关节炎中的细胞因子（分解代谢作用）和/或生长因子（合成代谢作用）。本研究的目的是研究白细胞介素-1 β（IL-1β）和胰岛素样生长因子I（IGF-I）和II（IGF-II）对人骨关节炎软骨细胞中HIF-1α的调节，并确定磷脂酰肌醇-3-激酶（PI-3 K）通路在此过程中的参与。用IL-1β、IGF-I和IGF-II以及PI-3 K的特异性抑制剂LY 294002刺激人骨关节炎软骨细胞。核蛋白水平和基因表达分别通过蛋白质印迹和定量逆转录聚合酶链反应分析。IL-1β在蛋白水平上调HIF-1α表达，但在基因水平不上调。IGF-I处理导致HIF-1α的蛋白和mRNA水平增加，而IGF-II对其表达无影响。然而，所有这些刺激都利用了PI-3 K通路。IL-1β在转录后水平上调HIF-1α蛋白水平，而IGF-1在转录水平上调HIF-1α。相反，IGF-II不影响HIF-1α的蛋白或基因表达水平。此外，所有测试的刺激都在一定程度上利用了PI-3 K通路。基于这些发现，我们能够表明，缺氧诱导因子-1在骨关节炎的软骨细胞中表现出保护活性。
Hypoxia-inducible factor 1 alpha regulates genes related to cellular survival under hypoxia. This factor is present in osteroarthritic chondrocytes, and cytokines, such as interleukin-1 beta, participate in the pathogenesis of osteoarthritis, thereby increasing the activities of proteolytic enzymes, such as matrix metalloproteinases, and accelerating cartilage destruction. We hypothesize that Hypoxia Inducible Factor-1 alpha (HIF-1α) can regulate cytokines (catabolic action) and/or growth factors (anabolic action) in osteoarthritis. The purpose of this study was to investigate the modulation of HIF-1α in human osteoarthritic chondrocytes by interleukin-1 beta (IL-1β) and insulin-like growth factors I (IGF-I) and II (IGF-II) and to determine the involvement of the phosphatidylinositol-3-kinase (PI-3K) pathway in this process. Human osteroarthritic chondrocytes were stimulated with IL-1β, IGF-I and IGF-II and LY294002, a specific inhibitor of PI-3K. Nuclear protein levels and gene expression were analyzed by western blot and quantitative reverse transcription-polymerase chain reaction analyses, respectively. HIF-1α expression was upregulated by IL-1β at the protein level but not at the gene level. IGF-I treatment resulted in increases in both the protein and mRNA levels of HIF-1α, whereas IGF-II had no effect on its expression. However, all of these stimuli exploited the PI-3K pathway. IL-1β upregulated the levels of HIF-1α protein post-transcriptionally, whereas IGF-I increased HIF-1α at the transcript level. In contrast, IGF-II did not affect the protein or gene expression levels of HIF-1α. Furthermore, all of the tested stimuli exploited the PI-3K pathway to some degree. Based on these findings, we are able to suggest that Hypoxia inducible Factor-1 exhibits protective activity in chondrocytes during osteoarthritis.
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